Method of fabricating a multichannel electrode

ABSTRACT

The invention provides a multichannel electrode (“MC electrode”) which can perform multiple functions such as recording, stimulating and lesioning simultaneously or sequentially upon a single insertion into a target site. In one aspect, the MC electrode further provides imaging and drug delivery capabilities. The invention also provides interface connectors for connecting the MC electrode to external units such as data acquisition and/or stimulation systems. Although the MC electrode and associated connectors and system(s) provide an optimal way to perform deep brain surgical procedures, the MC electrode and associated connectors and system(s) are useful generally in any technique which relies on recording, activating, and/or inhibiting electrical signals produced by cells.

RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.10/001,050, filed Oct. 31, 2001, now U.S. Pat. No. 7,010,356, theentirety of which is incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to a multichannel electrode comprising anon-planar backbone for use in medical procedures, particularlyneurosurgical procedures.

BACKGROUND OF THE INVENTION

During neurosurgical procedures, electrodes are commonly used to monitorelectrical activity and stimulate and/or lesion neural tissue.Typically, electrodes are brought into the vicinity of cell membranes sothat an electrical transition resistance (impedance) is created betweenthe cells and the electrodes. Electrical stimulation of a malfunctioningneuron can be used to activate or reversibly block neural activity,while lesioning can be used to permanently disable neuronal activity.U.S. Pat. No. 1,662,446, issued to Wappler, teaches an early electrodesystem.

The recent resurgence of procedures to stimulate and produce lesions indeep brain structures for the treatment of Parkinson's disease, tremor,and dystonia, has been due not only to a better understanding offunctional neuroanatomy of the cells involved in these diseases (Albinet al., 1995, Trends in NeuroScience 18(2): 63-4; Alexander et al.,1990, Prog. in Brain Res. 85: 119-46) but also to the development oftechniques for accurately localizing these cells (Lang et al., N. Engl.J. Med. 339(16): 1130-43). Microelectrode recording allows directrecording and characterization of the activity of neural cells and canbe used to record individual cells at a spatial interval from a micronto 100 microns and in a frequency range from 1 Hz to 200 Hz (see, e.g.,Albe-Fessard et al., 1963, Ann. Chir. 17: 1185-1214; Albe-Fessard etal., 1963, Electroencephalogr. Clin. Neurophysiol. 15: 1052; Jasper etal., 1963, Physiologist 7: 167).

While microelectrodes provide the best means of localizing diseasedcells, generally, microelectrodes must be inserted into the brainmultiple times (e.g., at target sites separated by about 2 mm) tosufficiently characterize the physiology of a region which is to bestimulated or lesioned. Probes comprising groups of microelectrodesbundled together at high density (“multichannel microelectrodes”)increase the resolution of individual recording passes, and canstimulate and record a 20-200 μm radius around an insertion site (see,e.g., Gross et al., 1999, Brain 122(Pt3): 405-16; Gross et al., 1999, J.Neurosurg. 90(3): 468-77; Ranck, 1975, Brain Res. 98: 417-440).Typically, a multichannel microelectrode is inserted at a location, andwhen a site of pathology is identified, it is removed and replaced by alarger diameter macroelectrode (e.g., about 1.1 mm) which is used tovalidate target location and for subsequent stimulating and/or lesioningas appropriate. However, even multichannel microelectrodes must beinserted and removed at least three to five times to obtain good targetlocalization and macroelectrodes generally must be inserted separately.

Multichannel electrodes which combine the recording functions ofmicroelectrodes and the stimulating functions of macroelectrodes havebeen reported. Generally, these systems consist of recording andstimulating wires which radiate from a planar backbone (see, e.g., U.S.Pat. No. 5,282,468). Because of the large surface area these electrodesoccupy, they generally are suited only for recording and stimulatingneurons at the surface of the brain and are not for use in deep brainprocedures.

SUMMARY OF THE INVENTION

The invention provides a multichannel electrode (“MC electrode”) whichcan perform multiple functions such as recording, stimulating andlesioning upon a single insertion into a target site. In one aspect, theMC electrode further provides imaging, drug delivery and therapeuticcapabilities. For example, the MC electrode can be used to providegrowth factors, chemotherapeutics, epilepsy drugs, and/or radiation orradiofrequency therapy to a target site.

The invention also provides interface connectors for connecting a firstend of an MC electrode to external units such as data acquisition and/orstimulation systems. Although the MC electrode and associated connectorsand system(s) provide an optimal way to perform deep brain surgicalprocedures, the MC electrode and associated connectors and system(s) areuseful generally in any technique which relies on recording, activating,and/or inhibiting electrical signals produced by cells.

In one aspect, the MC electrode according to the invention comprises anon-planar, substantially cylindrical backbone which comprises aplurality of electrode channels. Preferably, the backbone is flexible,or semi-flexible, and comprises a substantially conical or frustoconicaltip for ease of insertion at a site comprising one or more target cells.More preferably, however, the MC electrode has sufficient stiffness toavoid deviation from a stereotactic perspective.

In one aspect, the backbone comprises a non-conductive material. Inanother aspect, the backbone comprises a lumen. In a further aspect, thebackbone alternatively, or additionally, is capable of transmittinglight. For example, the backbone can be a light guide or an opticalfiber. In still a further aspect, the backbone is capable of deliveringan agent (e.g., such as a drug) to a site comprising one or more targetcells.

Preferably, the non-planar backbone comprises an electrically conductivelayer. In one aspect, the non-planar backbone is bonded to anelectrically conductive material and electrode channels aremicromachined or microlithographically etched into the electricallyconductive material. Preferably, the channels are micromachined by lasermicromachining or other methods. In another aspect, the non-planarbackbone comprising electrode channels is contained partially within aprobe housing with at least its tip exposed. The probe housing can bedesigned to facilitate handling by a user and for connection to a drivesystem used to activate and control the movement of the MC electrode.Preferably, the MC electrode can be advanced and retracted and/orrotated to enhance its ability to localize a target. This can beachieved by providing an interfacing connector in communication with amicrodrive device.

Preferably, the MC electrode comprises sets of channels, each setcomprising at least two, and preferably, at least four electrodechannels. In a preferred aspect, at least two of the channels in eachset are at least partially non-coplanar relative to each other.

In one aspect, the backbone of the MC electrode comprises a second endcomprising a conical or frustoconical tip. The tip comprises a baseportion adjacent to a substantially cylindrical portion of the backboneand a tip portion comprising a diameter which is smaller than the baseportion. The electrode comprises at least one set of four channelsdisposed on the backbone. At least one channel extends past the baseportion of the tip while at least one channel does not extend past thebase portion of the tip.

Each set of channels preferably performs a specific function, such asrecording or stimulating/lesioning. Preferably, the MC electrodecomprises at least one set of channels for recording (“recording channelsets”) and at least one set of channels for stimulating and/or lesioning(“stimulating/lesioning channel sets”). Still more preferably, aplurality (i.e., at least two) of recording channel sets andstimulating/lesioning channel sets are provided.

In a preferred aspect of the invention, sets of four electrode channelsor “quadraelectrodes” are disposed on the non-planar backbone and atleast two of the channels are at least partially non-coplanar with eachother. Preferably, at least three of the channels are on a single planewhile the fourth channel is at least partially on a different plane. Inone aspect of the invention, the quadraelectrodes are either recordingtype quadraelectrodes (RTQs) or stimulating type quadraelectrodes(STQs). Generally, RTQs do not perform stimulating or lesioningfunctions while STQs do not perform recording functions. However,preferably STQs have both stimulating and lesioning capabilities.

Preferably, RTQs record from all four channels simultaneously, providingan electronic signature or image of one or more neurons in proximity tothe RTQ to allow the precise localization of the one or more neurons.The directionality of a plurality of signal sources also can bedetermined. By precise resolution of the multiple signals recorded, afunctional map or image of a population of neurons being studied can beobtained. This functional map can be correlated with a patient'ssymptoms and can be used to determine appropriate STQs to use tostimulate the appropriate populations of neurons.

Generally, STQs comprise at least one channel with a positive polarityand at least one channel with a negative polarity. Combinations of threepositive channels and one negative channel, three negative channels andone positive channel, or two negative channels and two positive channelscan be provided.

In one aspect, the sets of electrode channels are electrically insulatedfrom each other. Individual electrode channels also may partiallycovered by an insulating material. For example, the channels can becovered over the cylindrical portion of the backbone and exposed atleast partially at the conical or frustoconical tip portion of thebackbone.

The invention also provides methods for fabricating a multichannelelectrode. In one aspect, the method comprises the steps of: providing anon-planar backbone, coating the non-planar backbone with anelectrically conductive material, and laser micromachining a pluralityof channels into the electrically conductive material. Preferably, theelectrically conductive material is bonded to the non-planar backbone bydirect deposition techniques or by coating an adhesive layer onto thebackbone. Preferably, at least one channel comprises an impedancesuitable for recording electrical activity of a cell, and at least onechannel comprises an impedance suitable for stimulating the electricalactivity of a cell.

In one aspect, the invention provides a multichannel electrodecomprising:

a first non-planar backbone comprising a lumen, and a second non-planarbackbone disposed within the lumen of the first non-planar backbone. Thefirst and second backbone each comprise at least one electrode channel,wherein at least one of the channels has an impedance suitable forrecording an electrical signal from a cell, while at least one other ofthe channels has an impedance suitable for electrical stimulation of acell.

In another aspect, the multichannel electrode comprising the first andsecond backbone comprises one or more sets of channels, wherein at leastone of the sets of channels has an impedance suitable for recording andat least one of the sets has an impedance suitable for stimulating. In afurther aspect, a set can comprise at least two channels, at least onechannel being on the first backbone and at least a second channel beingon the second backbone.

The first and second backbone can be machined separately. However, thefirst and second backbone also can be formed by rolling a flat planarsheet which channels have been machined around a central fiber. Thecentral fiber itself can comprise one or more channels.

The invention also provides an interfacing connector for interfacing theMC electrode with one or more external systems, such as an interfacingcable, drives, processors, multi-channel stimulation units, lightsources, detectors, oscilloscopes, fluid delivery pumps, suctiondevices, filters, a power supply, radiation treatment sources,amplifiers, displays, implantable source devices (e.g., providingstimulating and recording functions for use in chronic therapies) andthe like. In one aspect, the interfacing connector is coupled to the oneor more external devices by means of the interfacing cable.

In one aspect, the interfacing connector comprises a plurality of wires,each wire connected to a channel of the multichannel electrode at oneend and connectable to at least one external system at another end.

In another aspect, the connector comprises a substantially cylindricalhousing with a first and second end and an outer wall. A plurality ofcentral terminals radiate from the other wall to form an inner walldefining a lumen. The central terminals form electrical contacts withthe plurality of channels of the MC electrode. The first end of theinterfacing connector housing receives the MC electrode in the centralopening, while the second end of the interfacing housing is coupleableto at least one external system.

Preferably, a processor which is in communication with the interfacingconnector (either directly or via the cable) is used to send and receivesignals to other external components of the system and can direct theactivity of the MC electrode in response to these signals. For example,the processor can be used to regulate the recording andstimulating/lesioning functions of the sets of electrode channels of theMC electrode. The processor also can be used to control the motion ofthe MC electrode in response to optical data and/or electrical datareceived from one or more neural cells. In a preferred aspect, theinterfacing connector comprises components for enhancing or regulatingelectrical signals sent or received by the channels of the electrode.For example, the interfacing connector can comprise resistors incommunication with the channels for modulating the impedance of thechannels so that a particular set of channels functions optimally as arecording channel set or as a stimulating channel set, respectively. Theinterfacing connector also can comprise one or more preamplifiers foramplifying signal received from a recording channel set.

In one aspect, the non-planar backbone of the MC electrode comprises afirst end and a second end and is at least partially transparent. Thefirst end is in optical communication with a light source (e.g., such asa laser, a non-coherent light source, and the like) while the second endcomprises the conical or frustoconical tip portion of the electrode. Thebackbone provides a light path for transmitting light from the lightsource to a target and for receiving light from the target. A receivedlight path can be coincident with, or separate from, a transmitted lightpath. For example, the backbone can be a light guide or an optical fiberor can comprise a bundle of light guides or optical fibers.

Preferably, a detector also is in optical communication with at leastthe received light path, and converts optical signals received intosignals (e.g., electrical signals) which can be translated into an imageof the target site. Preferably, the processor is used to display thisimage on the display of a user device (e.g., such as a computer) coupledto the processor, enabling a user of the electrode to visualize thetarget site and adjust the movement and/or activity of the electrode asnecessary.

In one aspect, the backbone is hollow to facilitate the transmission oflight (e.g., the backbone itself can be a hollow optical fiber toprovide annular ring light). In another aspect, a light path is providedin the form of a fiber which is itself placed within the hollowbackbone. In still another aspect, bundles of optical fibers areprovided within the lumen of the hollow backbone. In a further aspect, abackbone is provided which comprises a groove or channel along its sideinto which a light guide or optical fiber can be fitted. The light guideor fiber can be coupled to a camera to facilitate the imaging process.

When the backbone is hollow, a pump can be coupled to a first end of thebackbone or to a portion of the interface connector, to facilitate thetransport of fluids through the lumen of the backbone. In this way, theMC electrode also can be used as a drug delivery device or to provideirrigation fluids to wash a target site. However, a delivery device inthe form of a hollow flexible capillary or hollow needle also can beinserted into the lumen of the backbone and connected to the pump. Thedelivery device also can be fitted into a groove or channel along theside of the backbone.

Preferably the interfacing connector is connected or connectable to adrive mechanism which controls guided precise movement of the electrodeduring surgical procedures and chronically once the MC electrode is leftin situ.

In one aspect, the processor is part of a data acquisition system whichimplements one or more programs for analyzing electrical signalsobtained from one or more neurons at a target site and forcharacterizing the one or more neurons as diseased or healthy. In apreferred aspect, the processor is capable of characterizing a pluralityof signals obtained simultaneously from different sets of channels inthe multichannel electrode and even from groups of multichannelelectrodes. In one aspect, the processor displays the output of thisanalysis on the display of a user device (e.g., a computer) connectableto the network.

In one aspect, the data acquisition system is in communication with theMC electrode and, in conjunction with the processor, captures andprocesses neuronal signals acquired by the MC electrode. Preferably, theprocessor conditions or instructs the data acquisition system to captureneuronal signals at selected times.

The invention also provides a method for acquiring neuronal activitydata from a subject comprising the steps of: sensing neuronal signalsgenerated by a subject as the subject performs a task, recording atleast one physical condition of the subject while the task is beingperformed, and correlating the neuronal signals with at least onerecorded physical condition to yield anatomical information concerningstructures from which the neuronal signals originate.

The MC electrodes according to the invention can be used for acute orchronic treatment regimens. For example, where chronic stimulation ofone or more cells is desired (e.g., in the treatment of chronic pain) orwhere long-term monitoring is required (e.g., for an individual withseizures), the MC electrode can be coupled to a source device (e.g., astimulator/recording device) via percutaneous leads which are connectedto the interfacing connector. Preferably, leads are placed within abiocompatible, sterilizable, flexible or semi-flexible sheath. Thesource device preferably comprises a battery for providing a source ofpower to the MC electrode and/or a microprocessor for providinginstructions to the MC electrode to perform selected recording and/orstimulating functions. However, in another aspect, the microprocessor ispart of an extracorporeal device which is controlled by the patient or ahealth care worker.

The invention further provides a method of monitoring the activity ofone or more cells at a target site by recording electrical potentials ofthe one or more cells and/or modulating the activity of one or morecells. In one aspect, the method comprises bringing an MC electrode asdescribed above in electrical proximity to the one or more cells andrecording the activity of the one or more cells using at least onerecording channel set (e.g., such as an RTQ) of the MC electrode.Preferably, this recorded activity is compared to the activity of a cellwith one or more known physiological properties (e.g., a non-diseasedneural cell). In one aspect, the recorded activity is used to determinethe anatomical location of one or more malfunctioning cells. In apreferred aspect, after determining the anatomical location of the oneor more malfunctioning cell, at least one other set of channels (e.g., astimulating/lesioning channel set, such as an STQ) is activated todeliver an electrical stimulus to the one or more cells. In one aspect,the stimulus is used to activate the one or more cells. In anotheraspect, the stimulus is used to inhibit the one or more cells. In afurther aspect, the stimulus is used to disable or lesion the one ormore cells.

Preferably, a processor in communication with the MC electrode is usedto control the movement and activity of the electrode. In a particularlypreferred aspect, the MC electrode is used to image a target site andthe processor moves and/or alters the activity of the electrode inresponse to an image obtained (i.e., automatically, or in response toinstructions from a user).

The method of the invention can be used to treat of a number ofneurological disorders including, but not limited to, motor dysfunction,spasticity, Parkinsonism, tremors, dystonia, mood disorders, hypothalmicobesity, incontinence, chronic pain, spinal cord injuries, epilepsy, andthe like.

In one aspect, the MC electrode is used in an acute treatment bybringing the MC in proximity to one or more cells, localizing targetcells in need of such treatment (e.g., using at least one RTQ), bringingthe MC in closer proximity to the cells if necessary, activating orinhibiting the activity of the target cells or disabling the targetcells (e.g., using at least one STQ), and removing the MC electrode fromthe proximity of the target cells.

In another aspect, the MC electrode is used in a chronic treatment bybringing the MC in proximity to one or more cells, localizing targetcells in need of such treatment (e.g., using at least one RTQ), bringingthe MC electrode in closer proximity to the cells if necessary, andactivating or inhibiting the activity of the target cells (e.g., usingat least one STQ). Preferably, the MC electrode remains in proximity tothe target cells to monitor the activity of the target cells and tostimulate the cells as necessary to maintain a desired state of thecells.

In addition to using the MC electrode in methods of treatment, the MCelectrode can be used to detect the presence of, or monitor theprogression of, abnormal physiological activity in a cell. In a furtheraspect, the MC electrode is used to monitor the electrical activity ofcells at a target site in order to control drug delivery to the targetsite.

BRIEF DESCRIPTION OF FIGURES

The objects and features of the invention can be better understood withreference to the following detailed description and accompanyingdrawings. The drawings are not to scale.

FIG. 1 depicts a close up of sets of electrode channels on an opticalfiber backbone according to one aspect of the invention. In this Figure,each set or “quadraelectrode” comprises four channels. The larger starsrepresent quadraelectrodes for recording electrical potentials (“RTQs”)while the smaller stars represent quadraelectrodes used for stimulatingand/or lesioning (“STQs”).

FIG. 2 shows an MC electrode comprising an optical fiber backbone withmultiple alternating RTQs and STQs.

FIG. 3 is a schematic of an interfacing connector according to oneaspect of the invention for connecting an MC electrode to a dataacquisition system and to a drive for activating and controlling themotion of the electrode. The center of the connector is for connectingto the MC electrode. The connector comprises a contact point for eachchannel on the MC electrode. Ultrathin wires are used to connect a driveto the MC electrode.

FIG. 4 shows an aspect of the invention in which the MC electrodecomprises a cylindrical metal rod which is covered by a machinedgold-plated copper flex circuit board onto which channels are etched.

FIG. 5 shows the geometry of the tip of the MC electrode shown in FIG.4.

FIG. 6 is a graph showing change in current as a function of channelwidth.

FIG. 7 is a graph showing changes in voltage as a function of currentvariation through an MC electrode according to one aspect of theinvention.

FIG. 8 shows an animal connected to an MC electrode which is incommunication with a data acquisition system according to one aspect ofthe invention.

FIG. 9 shows an MC electrode according to one aspect of the inventionpenetrating the brain of a rodent.

FIG. 10 shows a single neuron spike (time 200 μs/div versus voltage 50μV/div) recorded using an MC electrode in vivo according to one aspectof the invention.

FIG. 11 is a flow chart showing the steps used to fabricate an MCelectrode according to one aspect of the invention.

FIG. 12 is a flow chart showing the steps of a method of using an MCelectrode in a chronic treatment regimen according to one aspect of theinvention.

FIG. 13 is a schematic diagram of a data acquisition system according toone aspect of the invention. The inset shows a schematic diagram of anRSI amplifier array forming part of the data acquisition system.

FIG. 14A shows an MC electrode according to one aspect of the invention,comprising a hollow backbone comprising a plurality of electrodechannels. The lumen of the hollow backbone comprises a smaller backbonewhich can itself be hollow and which comprises additional channelsdisposed thereon. FIG. 14B shows an embodiment in which the smallerbackbone comprises a plurality of optical fiber bundles and a centralcore which can be used to deliver radiation treatment or a drug to atarget site.

FIG. 15 is a schematic showing an interfacing cable according to oneaspect of the invention for interfacing the interfacing connector (andthrough it the MC electrode) to one or more external systems.

FIG. 16 is a schematic illustrating the multiple functions of an MCelectrode.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a multichannel electrode (“MC electrode”) whichcan record, stimulate and/or lesion upon a single insertion into atarget site. The MC electrode according to the invention can be used fortarget localization and for acute or chronic neuromodulation therapy.The invention further provides interface connectors and cables forconnecting the MC electrode to external units such as data acquisitionand/or implantable source devices where part of a chronic monitoringand/or treatment regimen.

DEFINITIONS

The following definitions are provided for specific terms which are usedin the following written description.

As used herein, “a multichannel electrode” refers to a non-planarbackbone comprising a plurality of electrode channels disposed thereon,wherein at least one of said channels has an impedance suitable forrecording an electrical signal from a cell and wherein at least oneother channel has an impedance suitable for electrical stimulation of acell.

As used herein, “flexible or semi-flexible” refers to an ability of abackbone to bend to an angle from 5°-45° relative to its longitudinalaxis. Flexibility can vary depending on backbone length and diameter.

As used herein, a “light path” is a path through which light can passfrom a light source to a target and/or from a target to a detector.

As used herein, “at least partially non-coplanar channels” refer tochannels which lie at least partially on different planes, i.e., atleast 5-50 μm of the length of each channel lies on different planes.

As used herein, a backbone which is “substantially cylindrical” refersto a non-planar backbone comprising a uniform diameter over at least 50%of its length.

As used herein, “a conical or frustoconical tip” refers to a tipcomprising a base portion and a tip portion comprising a diameter whichis smaller than the base portion (preferably at least two timessmaller). A conical tip has a pointed tip end while a frustoconical tiphas a flattened tip end.

As used herein, an “impedance suitable for recording” refers to animpedance which ranges from 200 kilo ohms to one megaohm, or greater

As used herein, an “impedance which is suitable for stimulating and/orlesioning” refers to an impedance which is less than or equal to 200kilo ohms.

As used herein, the term, “in communication with” refers to the abilityof a system or component of a system to receive input data from anothersystem or component of a system and to provide an output in response tothe input data. “Output” may be in the form of data or may be in theform of an action taken by the system or component of the system.

As used herein, “coupled to” refers to a physical connection between onecomponent of a system and another which can be direct or indirect.

As used herein, an electrode in “electrical proximity” to a cell refersto a distance which is sufficiently close to transmit electrical stimulito the cell or receive electrical signals from the cell.

As used herein, a “known physiological property” refers to at least aproperty which is indicative of the normal functioning of a cell, suchas an electrical activity which falls within normal limits of a normallyelectrically active cell (e.g., as determined by routine statisticaltesting using methods known in the art, setting confidence levelsgreater than or equal to 95%) or which is statistically significantlydifferent from normal limits and which is associated with a diseasestate. The normal electrical activity of a cell will vary with the typeof cell and can be determined empirically in a patient who exhibitsnormal responses to stimuli. In one aspect, “normal electrical activity”refers to voltages between 100 μV to 2 mV, and frequencies between 2 Hzand 200 Hz.

As used herein, “neural activity” refers to any physical behavior,output or phenotype of a neuron. For example, neural activity can bemeasured as one or more of the following parameters: action potential;depolarization; hyperpolarization; field potential; a behavior (e.g.,motion, ability to respond to visual and/or auditory cues; a seizure);speech; sight; a product of a neuron (e.g., a hormone, growth factor,neurotransmitters, ions, and the like), etc.

As used herein, a “stimulus which activates a cell” is one whichincreases the power of the cell by at least two-fold or 50%. Power iscalculated as the integral of the area under the curve of a recordedaction potential and is inversely proportional to the distance of the MCelectrode from the cell. Power also can be used to obtain an estimate ofthe distance of a signal source (e.g., one or more neurons) from the MCelectrode.

As used herein, a “stimulus which inhibits a cell” is one whichdecreases an action potential by at least 50%.

As used herein, a “stimulus which permanently disables a cell is onewhich permanently prevents a cell from generating an action potential.As used herein, an “acute treatment” is a treatment which lasts lessthan 24 hours.

As used herein, a “chronic treatment” is a treatment which lasts longerthan 24 hours.

As used herein, “changing the amount of an agent provided to a targetsite” or “changing the amount of a drug provided to a target site”refers to an increase or decrease in concentration, bolus size, or flowrate provided to the target site.

As used herein, “normalizing electrical activity” refers to changingelectrical activity to an amount of activity which is less than 10%,preferably, less than 5%, and still more preferably, less than 2.5% or1% different from the activity defined for a normal cell, a normalpopulation of cells, or normal cells in a population of normalindividuals.

As used herein, a “detector” is a device capable of detecting one ormore desired optical properties of an area of interest. Suitable opticaldetectors include any type of photon detector, such as photodiodes,photomultiplier tubes, cameras, video cameras, CCD cameras, and thelike.

As used herein, “optical imaging” refers to the acquisition, comparison,processing and/or display of data representative of one or more opticalproperties of an area of interest. Optical imaging may involveacquisition processing and display of data in the form of images, butneed not. For example, an optical image may be a display of spectralinformation acquired from a target site.

MC Electrode

In one aspect, an MC electrode according to the invention comprises anon-planar, backbone which comprises a plurality of electrode channels.Preferably, the backbone is a substantially cylindrical structure whichis tapered at one end to form a substantially conical or frustoconicaltip (see, e.g., as shown in FIG. 1) to facilitate its insertion at asite comprising one or more target cells (e.g., such as the brain,spinal cord, or a neural ganglia). Preferably, the outer diameter of theMC electrode (including backbone and channels) is less than 1.8 mm,preferably, less than 1.5 mm, still more preferably less than 1 mm, lessthan 0.8 mm, less than 0.7 mm, less than 0.6 mm, or less than 0.5 mm.The length of the electrode can vary depending on its application;however, in one aspect, the length of the MC electrode ranges from 5 mmto 10 cm. Preferably, the tip portion of the MC electrode is from about0.05 to 4 mm.

In certain embodiments, the tip can comprise a radiopaque marker tofacilitate localization of the position of the tip relative to one ormore target cells. Radiopaque markers can be made from gold, tantalum,platinum, iridium material, and the like, which can be bonded to the tipusing methods known in the art. In one aspect, the non-planar backboneof the MC electrode is a rod, fiber, or cable, which tapers at its end.Preferably, the backbone comprises a non-conductive material, such asglass, quartz, or a polymer or copolymer such as plastic, methacrylate,acrylate, polystyrene, polycarbonate, polyurethane, monovinylidene,PMMA, conducting polymers, polyimide, and the like. Less preferably, thebackbone comprises a metal. In one aspect, the backbone is at leastpartially flexible, or semi-flexible (e.g., the backbone can bend to anangle of preferably 45° or less with respect to its or originallongitudinal axis) to facilitate its use as a probe.

In another aspect, the MC electrode comprises more than one backbonecomprising channels. For example, as shown in FIGS. 14A and 14B, in oneaspect, the MC electrode comprises a first hollow backbone into which asmaller, second backbone fits. Both the first and second backbone cancomprise electrode channels, thereby maximizing the number of electrodechannels that can be provided as part of the MC electrode. Preferably,fibers can be adjusted telemetrically to different lengths to recorddata at different distances and locations.

In a preferred aspect, the backbone provides an optical path throughwhich light can be transmitted from a light source to a target site(e.g., a site comprising one or more neural cells) and through whichlight can be received from a target site. For example, the backbone canbe a light guide or an optical fiber (e.g., such as a plated surgicalgrade optical fiber). In one aspect, therefore, the backbone comprisesan optically transmissive core (e.g., having a refractive index of1.41-1.62) surrounded by a cladding. The cladding facilitates lightguiding by the core and also provides any necessary rigidity to thecore. The materials of the cladding can vary, although the cladding alsoshould be light transmissible. Preferably, the refractive index of thecladding is at least 0.5, at least 1, at least 2, at least 3, at least5% less, or at least 10% less than the refractive index of the core. Thecladding material should also adhere to the core material such thatrepeated flexing and bending of the backbone does not cause delaminationat the interface between the core and cladding material. Preferably, thecladding is thermoplastic to withstand variations of temperatures duringetching or micromachining of electrode channels onto the backbone.

In one aspect, the backbone is hollow and comprises the light pathwithin its lumen. For example, one or more optical fibers or lightguides as described above can be placed within the lumen (see, as shownin FIG. 14B). However, in another aspect, the backbone itself forms ahollow optical fiber. In this aspect, the backbone can comprise an innerhollow cylinder which functions as a core and which is surrounded by anouter cylindrical layer which functions as a cladding. In still otheraspects, the backbone comprises a channel or groove on its outer surfaceinto which an optical fiber or light guide can fit. The optical fiber orlight guide in this embodiment can be used to receive opticalinformation relating to the electrode itself, in addition to opticalinformation relating to target cells in proximity to the electrode. Forexample, the optical fiber or light guide can be used to image the tipof the electrode when a radiopaque marker is affixed to it, to enable auser to more precisely determine the position of the electrode relativeto one or more target cells.

The hollow portion of the backbone or a portion thereof which is notoccupied by the light path can be used to supply fluids to a targetsite. In one aspect, a fluid is provided which comprises an agent suchas a chemotherapeutic agent, radioactive agent, radiosensitizer, atrophic factor (e.g., a neurotrophic factor), antibiotic, hormone,steroid, growth factor, neurotransmitter, an agonist, or antagonist of aneurotransmitter, a symphathomimetic, a metabolite, cell (e.g., such asa stem cell), sedative, anti-epileptic (e.g., acetzolamide, amphetamine,carbamazepine, chloropromazine, clorazepate, dextroamphetamine,dimenhydrinate, ephedrin, divalproex, ethosuximide, magnesium sulfate,mephenytoin, metharbital, methsuximide, oxazepam, paraldehyde,pamethadione, phenacemide, phenobarbital, methsuximide, phenytoin,primidone, trimethadione, valproate, etc.), atherapeutic polypeptideand/or a nucleic acid encoding the same, an antibody which specificallyrecognize a tumor antigen, and combinations thereof.

Radiosensitizers include those agents which, when present duringirradiation, enhance the cytotoxic effects of radiation, e.g., such asionizing radiation. For example, the hypoxic radiosensitizerMisonidazole enhances the cytotoxic effect of X-ray and gamma rayradiation. 5′-bromo-2′-deoxyuridine (BUdR) or 5′-iodo-2′-deoxyuridine(IUdR) can be used to sensitize DNA to breakage by ionizing orultraviolet radiation. Various heterocyclic compounds, in particular,those with oxidized nitrogen moieties, can be used for the purpose ofradiosensitizing diseased cells such as tumor cells (see, e.g., Asquithet al., 1974, Radiation Res. 60: 108-118; Hall et al., 1978, Brit. J.Cancer 37: 567-569; Brown et al., 1980, Radiation Res. 82: 171-190; andU.S. Pat. No. 4,371,540), as can 1-substituted 3(5)-nitro-s-triazoles,quinoxaline-1,4-dioxide derivatives, diamines such asdiaminetetrametronidazoles (DATMs) (see, e.g., U.S. Pat. No. 5,700,825),and texaphyrins (U.S. Pat. No. 5,622,946).

Chemotherapeutic agents include those chemical and biological agentssuch as peptides, proteins, lymphokines, antibodies, tumor necrosisfactor, conjugates of antibodies with toxins, and other chemical orbiological molecules which have an antitumor effect which is oxygendependent. Chemotherapeutic agents include, but are not limited to:alkylating agents, such as Melphalan (PAM); Cyclophosphamide (CTX);cis-Diammminedichloroplatinum (II) (CDDP); nitrosoureas, such as N,N′-bis(II-chloroethyl)-N-nitrosourea (BCNU), nitrogen mustards;ethyleneimine compounds; alkyl sulphonates; cisplatin; dacarbazine; andthe like. Antimetabolites, such as folic acid, purine or pyrimidineantagonists, 6-Mercaptopurine, 5-fluorouracil (5-FU),fluorodeoxyuridine, cytosine arabinoside, methotrexate and thioquinonealso can serve as chemotherapeutics. Antibiotics including, but notlimited to, actinomycin, daunorubicin, adriamycin and bleomycin andmitotic inhibitors, such as the vinca alkaloids (e.g., etoposide,vincristine and vinblastine and derivatives of podophyllotoxin) also canbe used. Chemotherapeutic agents are described further in Gralla et al.,1984, Cancer Treatment Reports 68(1): 163-172. Mixtures of more than onechemotherapeutic or radiosensitizer agent also can be administered.

Toxins, such as neurotoxins, also can be delivered to a target site, forexample, when it is desirable to eliminate malfunctioning cells.Preferably, the agent is selected to supplement the effects ofelectrical stimulation (i.e., whether to activate or inhibit theactivity of cell(s)).

A fluid also may be delivered and used to irrigate a site being treatedand may comprise physiological saline. Alternatively, or additionally,the fluid may comprise a radiopaque agent or contrast agent (e.g., suchas barium sulfate), for use in localizing the position of the MCelectrode tip relative to cells at a target site.

Imaging agents also can be delivered, such as lanthanide metal complexescomprising gadolinium, samarium or ytterbium, as well as metals known toexhibit similar chemistry such as yttrium, indium and gallium.Radioactive tracer molecules also can be used.

Preferably, the end of the backbone distal from the tip is incommunication with a pump which provides sufficient pressure to deliverthe fluid to the target site. The operation of the pump can be manuallycontrolled by a user or can be controlled via instructions programmedinto a processor in communication with both the pump and the MCelectrode. Alternatively, or additionally, the pump can be provided witha microprocessor for providing instructions to the pump.

Preferably, the backbone of the MC electrode further comprises anelectrically conductive layer onto which a plurality of electrodechannels are disposed (e.g., by micromachining, described furtherbelow). The electrically conductive layer can comprise metal such asgold, copper, nickel, titanium, platinum, silver, silver-plated copper,silver tungsten, silver cadmium-oxide, silver tin-oxide,indium-tin-oxide, tin-oxide, and the like. The electrically conductivematerial can be bonded to the backbone using an adhesive undercoating,such as nickel/titanium. In a particularly preferred embodiment, acoating is used which is substantially transparent, yet stillconductive, such as indium-tin oxide, or tin oxide. For example, thismay be desirable to allow an MC electrode which comprises a light pathto transmit light along its length as well as at its tip.

The conductive material comprises a plurality of electrode channels.Preferably, the plurality of electrode channels are organized into setsof channels, each set comprising at least two, and preferably, at leastfour channels. Each set is separated from the other by a region ofinsulating material such that there is no electrical cross-talk betweensets of channels. The insulating material may include, for example, anymaterial having a dielectric constant greater than that of the electrodechannel metal, and materials, such as glass fiber, silicon elastomers,or like material, having a high dielectric constant can be used. In oneaspect, substantially all of the channels also are covered by insulatingmaterial except for region(s) at the tip (e.g., of about 2 to 5 μm) toprovide “open contacts” or surfaces through which electrical current canpass and be received. In a currently preferred embodiment, the MCelectrode is coated with an insulating material such as polyimide orTeflon® to isolate individual channels and enhance the biocompatibilityof the electrode (e.g., to reduce biological rejection/inflammatoryresponses). Coating thickness can vary so long as the proper/desiredamount of insulation is obtained.

Each set of channels performs a specific function such as recording orstimulating/lesioning. Preferably, the MC electrode comprises at leastone set of channels for recording (“a recording channel set”) and atleast one set of channels for stimulating and/or lesioning(“stimulating/lesioning channel set”). Still more preferably, aplurality (i.e., at least two) of recording channel sets andstimulating/lesioning channel sets are provided. Recording andstimulating can be performed sequentially according to a user'spreference as described further below.

The overall diameter of the MC electrode will ultimately depend on thenumber of and spacing of channels which are placed on the non-planarbackbone, the spacing between sets of channels and the width ofindividual channels. These parameters in turn depend on the desired usefor the MC electrode. For example, the tip size determines the abilityof the MC electrode to resolve separate signal sources (e.g., neurons)and to obtain electronic signatures of one or more cells, while thechannel width determines the electrical properties of the channel (e.g.,its ability to stimulate or record).

The lower limit on channel size is generally the lower limit on the sizeof a cell or group of cells to be stimulated or whose action potentialsare to be recorded, and, generally, the size of the electrode channeltip, or open contact surface, should be at least ½ to ⅓ of the size ofthe cell. A typical neuron generally is on the order of 10 μm to 100 μmand therefore, in one aspect, a lower limit on channel tip or opencontact surface size may be set at greater from an amount greater than 0to 10 μm in width. This is particularly desirably, when the channel ispart of a recording channel set for obtaining high-resolution data fromsingle neurons. However, it may be less desirable to provide stimulatingelectrodes which can only stimulate single neurons at a time, andtherefore the channels at the tip or open contact surface instimulating/lesioning sets are preferably larger than 10 μm, i.e., onthe order of 11-30 μm and preferably, 20-30 μm in width.

Generally, whether a recording channel set or stimulating channel setfunctions to record or stimulate, respectively, depends on the impedanceof the set. Impedance is a measure of a material's resistance tocarrying an electrical current and can be controlled at least in part bycontrolling the dimensions of the channels, as described above. Forexample, recording channel sets have a high input impedance (greaterthan or equal to 200 kilo ohms to 1 megaohm) as a result of the smalldiameters of their channels while stimulating channel sets have lowerimpedance (less than 200 kilo ohms) as a result of their larger channelcross section. Impedance further can be modulated by providingmicroresistors in communication with the sets of channels at an end ofthe electrode distal to the tip (i.e., as part of the interfacingconnector described further below). The ratio between exposed andinsulated regions of the channels also affects impedance during use.Generally, the larger an exposed region is compared to an insulatedregion, the lower the impedance value which can be expected. Impedancescan be measured and optimized as is routine in the art, e.g., byobtaining measurements in phosphate buffered saline using an HP 4194AGain/Phase analyzer or other impedance measuring device

Generally, a recording channel set cannot be used effectively tostimulate (except to micro-stimulate or to stimulate an evoked actionpotential for recording purposes) and a stimulating channel set cannotbe used effectively to record. However, a stimulating channel set alsocan be used to lesion, the difference being that stimulating (e.g., toactivate or inhibit a neuron) is reversible while lesioning (e.g., todisable a neuron is not). Electrical discharges of relatively lowfrequency (e.g., about 50 Hz) are expected to excite nearby neural cellswhile those of relatively high frequency (e.g., about 200 Hz) areexpected to inhibit nearby neural cells. Repeated high frequencystimulation is expected to permanently disable or lesion a neural cell.

The ability to stimulate or lesion is dependent on the current andfrequency of the electrical discharge through the stimulating/lesioningchannel set. Stimulation generally requires low current (microamps) andfrequencies of up to about 200 Hz, while lesioning generally requireshigh currents of up to 2 milliamps with frequencies up to about 200 Hz.Frequency can be continuous or pulsatile.

In one aspect, a set of electrode channels is used to provide an RFsignal via connection to an RF output source and the RF signal isprovided at a frequency which can permanently disable a cell. See, e.g.,as described in U.S. Pat. No. 6,259,952. The RF output source can becoupled to one or more sets of electrode channels by means of theinterfacing connector described further below.

By providing more recording and stimulating sets which can be usedselectively (e.g., according to instructions from a processor incommunication with the MC electrode via an interfacing connector,discussed further below), the user has greater probability ofsuccessfully localizing target cell(s) (e.g., one or more diseasedneurons) and treating these (e.g., activating or inhibiting, ordisabling, i.e., lesioning) while minimizing the need to remove andre-insert the MC electrode. In a particularly preferred embodiment,there are 20-50 sets of four channels per set per a 0.5 mm diameterfiber. In one aspect, for example when the backbone is hollow, a smallerdiameter MC electrode may be fitted into the lumen of a larger MCelectrode, providing still more sets of channels (see, e.g., as shown inFIG. 14A). The smaller diameter electrode can comprise a light path fortransmitting light (e.g., the backbone of the smaller diameter electrodecan be a light guide or optical fiber or can provide anotherfunctionality such as a conduit for fluid delivery) (see, e.g., FIG.14B).

The multiple channels of the MC electrode can be located strategicallyon the fiber (see FIGS. 1 and 2) to maximize signal resolution byrecording electrodes and the range of a target site (e.g., size, numberof cells) that can be stimulated/lesioned. In a currently preferredembodiment, a group of four geometrically arranged channels is provided,forming a “quadraelectrode”. At least two of the set of four channelslie at least partially in a different plane (e.g., at least at the tip)and preferably, two of the set lie in the same plane (see, e.g., asshown in FIG. 1). In another aspect, at least three electrode channelslie on a single plane and the fourth electrode lies at least partiallyon a different plane (e.g., at least at the tip). This non-coplanararrangement gives the best resolution of neuronal signals inthree-dimensional space. As can be seen in FIG. 1, channel lines can bestaggered and at least one channel line placed in a geometricallydifferent plane to meet this non-coplanar criteria.

Other designs and variations of electrode tip geometries also arepossible which will maintain an at least partially non-coplanarconfiguration of at least two electrode channels. Other arrangements andmodifications may include a precisely telescoped arrangement of twofibers with sets of channels divided between the inner and outer fibersand a single fiber with serially micro-machined notches along its shaftthat will allow placement of the fourth electrode in a non-planararrangement. The concentric tube within a tube arrangement shown inFIGS. 14A and 14B also can be used to create a non-coplanar arrangementof channels. FIG. 14B shows a scenario in which at least one channel ofa set is on the first hollow backbone and at least one other channel ofthe set is on the second smaller backbone within the lumen of the firsthollow backbone.

For example, in one aspect, two hollow polyimide tubes, each pre-coatedor layer with a conducting material are provided. One tube fits withinthe hollow lumen of the other and recording channel sets and stimulatingsets are distributed on the tubes such that two channels of one set areon one tube and two are on the other tube, or three of the channels areon one tube and one channel is on the other tube. This configurationmaximizes the number of recording channel sets and stimulating channelsets that are part of the MC electrode. The central core of theinnermost tube additionally can house one or more fibers that have noelectrode channels but which can be used as a light path or as adelivery device to deliver one or more therapeutic agents (e.g., drugs,radioactive agents, chemotherapeutic agents, and the like).

A similar configuration can be obtained by providing a planar sheet ofpolyimide or other flexible material coated with a conducting materialand wrapping one or more of the sheets around a cylindrical shaft (e.g.,a tube or fiber) or simply rolling the sheet(s) to create a multilayeredstructure comprising two or more backbones for electrode channels. Oneor more light paths can be created in a central hollow lumen. Forexample, one or more optical fibers can be placed within the centralhollow lumen. Additionally, or alternatively, one or more hollow fiberscan be inserted into the central lumen to provide a conduit for deliveryof one or more therapeutic agents, as described above.

In a currently preferred aspect, the MC electrode according to theinvention has at least two types of quadraelectrodes. A “recording typequadraelectrode” (RTQ) preferably has high input impedance to record theaction potential of cells (e.g., such as neuronal signals) and todeliver micro-stimulation. Preferably, the geometry of channels at thetip of the MC electrode is orthogonal to the longitudinal axis of thefiber so that the cross-sectional planes of the electrode tips areperpendicular to the optical axis of the fiber with the separationspacing between individual tips being in the range of 5 to 50 μm ormore, and preferably being between 5-30 μm. In one aspect, theseparation between each of the four channels in the RTQ ranges from 2-10μm so that incoming signal will be registered by the four channels ofthe RTQ virtually simultaneously to provide four different electricalviews of the same signal. This allows localization of asignal-generating neuron in three-dimensions, which is crucial for theidentification of target cell(s).

Preferably, by recording from all four channels simultaneously, the RTQprovides electronic signature or electronic “image” of one or moreneurons in proximity to the RTQ to allow the precise localization of theone or more neurons. In one aspect, the MC electrode records signalsfrom neurons 20 to 100 μm away from the tip of the MC electrode,enabling the electrode to record signals from up to 8-10 cells per RTQ.

Because data from all channels within an RTQ set are capturedsimultaneously, an electronic signature can be obtained for one or morecells, providing “a physiological image” of the one or more cells. Thisallows a user to produce a local functional map representing theactivity of cells (e.g., such as neurons) within a particular region oftissue being evaluated. For example, the geometry of channels at the tipof the MC electrode enables a user (e.g., via a processor incommunication with the electrode) to estimate the distance of one ormore cells from the tip of the electrode, enabling a user to define thefunctional geometry of tissue being evaluated with the MC electrode.This functional map can be correlated with an optical image obtainedfrom an MC electrode comprising one or more light paths, light focusingelements and/or cameras, as described above, and can be furthercorrelated with symptoms of the patient.

A “stimulating type quadraelectrode” (STQ) has relatively low impedanceto pass currents intermittently and preferably, to stimulate more thanone neuron at a time. The separation between each of the four channelsof the STQ is typically approximately 5 to 30

m wide. The current used to stimulate typically ranges from 100-500

A, while voltage preferably ranges from 1-5V.

Generally, STQs comprise at least one channel with a positive polarityand at least one channel with a negative polarity. Combinations of threepositive channels and one negative channel, three negative channels andone positive channel, or two negative channels and two positive channelscan be provided.

It should be obvious to those of skill in the art that MC electrodesaccording to the invention can have variable specifications with regardsto the fiber type, conductive material coating thickness, electrodesurface area and its current carrying capacity with respect to theelectrode geometry and feature size and size of channels. Variations canbe optimized and can be tested as in Example 1, below, and areencompassed within the scope of the invention.

Probe Housing

In one aspect, the MC electrode is at least partially contained within aprobe housing or casing to facilitate its handling. Preferably, as shownin FIG. 4, at least a tip portion of the MC electrode extends from atapered end of the probe housing. The probe housing generally is made ofa biocompatible, sterilizable material and further can comprise one ormore activating buttons connected to switches coupled to the interfacingconnector, for example, which can be used to activate one or morefunctions of the electrode (e.g., stimulating/lesioning, recording,imaging, drug delivery, and the like). The probe housing itself maycomprise multiple functionalities, e.g., such as fluid deliverydispensers, cameras affixed thereto, and the like, and in one aspect,the probe housing is removable from the MC electrode.

The probe housing also can comprise one or more radiopaque markers. Thismay be useful, for example, when an electrode tip, also comprising aradiopaque marker, is advanced or retracted or rotated within the probehousing, enabling a user to judge the relative amount of movement of thetip as the distance between a radiopaque marker on the tip and on theprobe housing changes.

Multiple MC electrodes also can be provided within a single probehousing and preferably, the movement of each of the electrodes can beindependently controlled, e.g., by providing each electrode with its owninterfacing connector as described further below.

Engineering the MC Electrode

In one aspect, the invention provides a method of producing an MCelectrode. Preferably, the method comprises obtaining a non-planarbackbone material which is substantially cylindrical, e.g., such as arod, a wire, a fiber, a cable, and which comprises a first and secondend. The first end is substantially flattened while the second endpreferably tapers to a tip. The tip portion of the backbone can beconical or frustoconical (e.g., having a flattened end). A tip also canbe fabricated from a backbone which is substantially entirelycylindrical and chamfered at the end. A tapered tip also can be producedusing a support structure to maintain the position of the backbone whilethe second end of the backbone is grounded and polished to a tip (see,e.g., as described in U.S. Pat. No. 6,257,971). When the backbonecomprises an optical fiber, the tip can be ground into a convex surfaceto create a focussing lens to enhance the imaging capabilities of theelectrode.

In a particularly preferred aspect, the non-planar backbone is anoptical fiber. Optical fibers are commercially available (see, e.g.,Corning® optical fibers, at www.corning.com/opticalfiber) but also canbe manufactured using methods known in the art. See, e.g., as describedin U.S. Pat. Nos. 6,243,520; 5,829,445; 5,755,850; 4,828,359, forexample. Polyimide tubing also can be used as can sheets of flexiblematerial which can be rolled to create the concentric tube structuresdescribed above.

As discussed above, the length and diameter of the backbone generallycan be varied from 5 mm to 10 cm in length and from 1.8 mm in diameter,to less than 0.6 mm in diameter, and including less than or equal to 0.5mm in diameter. In one aspect, a backbone greater than 10 cm in lengthis selected and cut to an appropriate size (e.g., by a laser or fibercutter).

In a preferred aspect, an adhesive coating of a conducting ornon-conducting material is layered onto the backbone, e.g., by dipping,immersion, thin or thick film deposition, electroplating,electrochemical plating, and the like. Preferably, the layer ofnon-conducting material ranges from 1 to 10 μm thick. If anon-conducting material is deposited, then an electrically conductivematerial is next layered onto the adhesive coating (e.g., byelectrodeposition, sputtering, and the like), preferably, within lessthan a minute after placing the adhesive coating on the non-planarbackbone. The layer of conductive material ranges from 1 to 20 μm thickand must provide a sufficiently uniform coating to transmit anelectrical signal from the second end of the MC electrode (e.g., thetip) to the first end of the MC electrode (e.g., the end proximal to theinterfacing connector).

To produce channels on the coated backbone, an improved lasermicro-machining technology was developed. Ultra precision lasermachining has emerged as an attractive tool for processing a myriad ofmaterials in various industrial fields and in medicine (Ogura et al.,1998, Laser Focus World 34: 117-18 and 120-3; Gower, “IndustrialApplications of Pulsed Laser Micromachining,” Proc. of the 1998International Symposium on Information Theory, CLEO/EUROPE'98; Nikumband Islam, “Precision Machining of Ceramics and Metals for ManufacturingApplications,” CAP Congress on Laser Material Processing and IndustrialApplications, University of Waterloo, Jun. 14-17, 1997). Thisdevelopment is mainly due to the rapid progress in the design of diodepumped solid-state lasers (see, e.g., Petersen and Nighan, “A HighPower, Diode-Pumped Solid State 355 Nm Laser System For MicromachiningApplications,” Conference on Lasers and Electro Optics CLEO-TechnicalDigest 1998; Nikumb et al., “Precision Machining Of Thin Metal FoilsUsing A Diode Pumped Solid State (DPSS) Laser,” Proceedings of the 17thInternational Congress on Applications of Lasers and Electro-Optics,ICALEO 98, Orlando, Fla., USA, Nov. 16-19, 1998). These lasers producepowerful light impulses with duration ranging from a few nanoseconds(10⁻⁹ s) to femtoseconds (10⁻¹⁵ s) (see, e.g., Kruger and Kautek, 1999,Laser Physics 9: 30-40; Chang et al., 1998, J. of Laser Applications 10:285-91; Nikumb and Islam, “Material Removal And Precision Machining OfCeramics Using ND:YAG Lasers,” 14th International Congress onApplications of Lasers and Electro-Optics 95 (ICALEO 95), San Diego,Calif., USA, Nov. 13-16, 1995, 168-77). Laser devices are now used inthin film synthesis, material processing, micro-fabrication,electronics, and biomedical and opto-electronics areas (see, e.g.,Nikumb and Islam, “Precision Machining Of Ceramics And Metals ForIndustrial Applications,” Canadian Association of Physicist (CAP)Conference, Waterloo, Ontario, June 1998).

Therefore, in one aspect, a laser beam is tightly focussed to a neardiffraction limited spot size and is used to machine channels of thedesired length and depth in the electrically conductive coating materiallayered onto the MC electrode backbone. Because the amount of heating isminimized by using a short pulse laser, backbone materials and theircoatings can be machined with ultra-fine accuracy.

Channel dimensions less than a few microns can be achieved with precisecontrol of work piece motion and proper choice of laser beam and factorswhich affect the proper choice of laser beams are known in the art anddescribed in Bordatchev and Nikumb, “Dynamic Calibration Of MotionSystem For Laser Micro-Machining,” NRC Research and TechnologyDevelopment Forum Magog, Quebec, Mar. 3-5, 1999, for example.Additionally, the machined depth and the surface finish of a machinedarea (e.g., such as a channel) can be controlled within the hightolerance values. Superfine microfeatures can be produced on complex,multi-layered materials (e.g., such as optical fibers) using anintegrated, computer-controlled, multi-wavelength, multi-axis laserprecision machining system as described in Zhou et al., 1995, “SensorsFor Intelligent Machining—A Research And Application Survey,”Proceedings of 1995 IEEE Conference on Systems, Man and Cybernetics,Vancouver, British Columbia, Canada, Oct. 22-25, 1995; Nikumb and Islam,1997, “Laser Depth Controlled Precision Machining Of Advanced Ceramics,”LASE '97, San Jose, Calif., February 1997, Proceedings of SPIE. LaserApplications in Microelectronic and Optoelectronic Manufacturing II(abstract 2991) SPIE: 176-82; and Nikumb and Islam, 1996, “DepthControlled Precision Machining Of Structural Ceramics Using Nd:YAGLasers,” Canadian Association of Physicists (CAP) Congress on LaserMaterial Processing and Industrial Applications, Ottawa, Ontario, Jun.16-19, 1996, for example.

In one aspect, laser machining of channels and generation of particulartip geometries is performed using the Master CAM package (available fromIn-house Solutions, Ontario). To achieve a high degree of accuracy withlaser micromachining, a fiber holding device is used in which themovement of the main body of the electrode is controlled usingrotational drives that are capable of rotational movement to within ±10nanometers. Preferably, a closed loop, camera-based vision system (e.g.,a coordinate measuring machine or CMM and sensing devices) withinspection-metrology software enables close monitoring and control ofchannel dimensions and connector feature sizes to within designedspecifications; e.g., as described above. Such systems are known in theart and available from Optical Gaging Products Inc. (OGP, Rochester,N.Y.); The L.S. Starrett Co. (Athol, Mass.); and Mitutoyo America Corp.(Aurora, Ill.). See, also, as described in Bloemhof et al., 2000, Porch.SIP 4007: 889-898. Such systems are available from Aerotech, Penn., andDover Instruments Corporation, Massachusetts, for example. In apreferred aspect, once channels are machined on the substantiallycylindrical body of the backbone and at the tip (as shown in FIG. 1),the electrode is at least partially coated with an insulating material,such as polyimide or Teflon®. Minimally, the spaces between sets ofelectrode channels should be coated to prevent cross talk between setsof channels. However, in one aspect, substantially all of the electrodeis coated except for the tip or a portion of the tip region of theelectrode to provide at least a surface of the electrode channels(“contact point”) exposed to provide stimuli to, or to receive actionpotentials from, a target site. If the entire fiber is coated, thenfurther micromachining of contact point(s) is performed on the coatedfiber. Small beam lasers are then used to open specified areas on thechannels as to create “open contact regions”. Portions of the MCelectrode also can be selectively coated with an insulating materialusing a mask.

As a final step, the MC electrode is interfaced with an interfacingconnector described further below.

Interfacing Connector

In one aspect, an interfacing connector is provided to couple the MCelectrode to various external devices and/or to modulate the function ofthe MC electrode. In a simple example, as shown in FIG. 4, aninterfacing connector can comprise a plurality of wires or leads, eachwire or lead connected to a channel at one end (shown in Figure) andconnectable to at least one external system at another end. For example,the wires/leads can be mounted and electrically connected to PC boardsusing ultrasonic bonding, wire bonding, laser joining or laser solderingtechniques, as is known in the art, and exposed connections can bestabilized or insulated with epoxy or another insulating material. Thepins on the PC board then can be mated directly to standard integratedcircuit sockets (e.g., such as DIP sockets) permitting easy handling andconnection (e.g., to preamplifiers and/or microdrives and/or processors,etc.).

In another aspect, a connector is provided which comprises a supportwhich holds an array of mating conductor pins (see, e.g., U.S. Pat. No.4,869,255), for making contact with each of the individual channels ofthe MC electrode. A connector with spring-loaded contact pins isdescribed in U.S. Pat. No. 5,560,358.

Preferably, the interfacing connector enables connection to a pluralityof external devices and can comprise additional functionalities formodulating the function of the electrode. FIG. 3 shows a cross-sectionthrough an interfacing connector according to a currently preferredembodiment. As shown in FIG. 3, in one aspect, the connector is agenerally cylindrical unit comprises a housing with an inner wall 1 andan outer wall 2 and having a first and second end (not shown).Preferably, the diameter of the connector housing is relatively small (5mm or less) so that at least a portion of it can be tunneled underneatha patient's skin from an incision site to an external exit site. Thefirst end of the interfacing connector is proximal to the first end ofthe MC electrode (e.g., the end distal to the tip portion), while thesecond end of the interfacing connector is coupleable to at least oneexternal device (e.g., such as a drive for controlling the movement ofthe MC electrode).

The inner wall 1 of the interfacing connector defines a central openinginto which the first end of the MC electrode is placed. Preferably, theopening is only slightly larger than the diameter of the first end ofthe MC electrode so that the electrode fits tightly within the opening(e.g., does not freely rotate unless manually forced to do so) and canform electrical contacts with each of a plurality of central terminals 3which extend from the outer wall 1 to form the inner wall 2. The centralterminals can be fabricated using a laser micromachining process.

Each central terminal 3 is fused to the longitudinal section of thedevice at the outer wall 1 and makes electrical contact with a channelin the MC electrode at least one point along the channel. Preferably,the portion of the central terminal 3 which contacts the channel isbonded to the channel and the portion of the central terminal 3 whichcontacts the outer wall is bonded or soldered to the outer wall. To jointhe connector to the main MC electrode body, perfect alignment withrespect to each channel line must be maintained. In one aspect, a devicewhich permits indexed rotation of the entire electrode-connectorassembly along a guide plate holder is used.

The connections between the MC electrode and the interfacing connectorhave different impedance depending the function of the channel (e.g.,whether the channel is part of a recording channel set, such as an RTQ,or a stimulating/lesioning channel set, such as an STQ). The inputimpedance of every channel can be changed at will (for example, duringan acute treatment procedure) by using variable micro-resistors on theconnector.

Standard or layered materials known in the art of electronics (e.g., vs.biocompatible materials) can be used for electrical connection and inthe bonding/soldering process since this part of the device is not indirect contact with the tissue area. For example, epoxy can be used asan insulating material in this portion of the device.

Preferably, as described above, the connector is interfaced at itssecond end to at least one external device. External devices within thescope of the invention, include, but are not limited to a drive ormicrodrive device, a processor (e.g., comprising a data acquisitionsystem), a light source, an oscilloscope, a detector, a fluid deliverypump, a suction device, an amplifier (e.g., a multichannel amplifier),filters, a power supply, and the like. External devices also can beprovided within the interface housing and coupled to the MC electrodevia the central terminals 3 of the interface connector. These devicescan be used to activate, disrupt, or otherwise modulate signals receivedor transmitted by the MC electrodes. Preferably, individual sets ofchannels can be controlled independently of other sets (e.g., RTQs canbe controlled independently of STQs, and individual RTQs and STQs can becontrolled independently of each other). For example, amplifiers,filters, and/or microresistors, as described above, can be providedwithin the interface housing.

In one aspect, the interfacing connector couples to the various externaldevices or systems through an interfacing cable such as the one shown inFIG. 15. The interfacing cable can comprise a plurality of concentrictubes for connecting with the electrical components of the interfacingconnector, the optical interface(s) of the interfacing connector, andthe portion of the interfacing device which is coupled to the deliverydevice or passage of the MC electrode. Preferably, the cable is flexibleand interfaces with the interfacing connector in such a way that itprovides electrical connectivity, optical interfacing for imaging, andcan modulate the delivery of agents, fluids, radiation, radiowaves, andthe like, through the MC electrode (e.g., via a pump, as describedfurther below).

More preferably, the cable provides a mechanism for registering andstoring or buffering electrical data (e.g., such as neuronal data) andcan transmit this data on demand (e.g., in a serialized fashion) to adata acquisition system as described further below. This enables thedevice to maximize the amount of useful information which can beobtained simultaneously from multiple channels of the electrode. Stillmore preferably, the cable is designed to be connectable to a pluralityof MC electrodes via their individual interfacing connectors. In oneaspect, when the MC electrode is part of a chronic treatment regimen,the cable is used to connect the MC electrode to an implantable sourcedevice stimulating and recording device described further below.

External Devices

Microdrives

Preferably, the connector is interfaced with a drive unit (e.g., such asa microdrive) for controlling the motion and/or advancement of the MCelectrode through a tissue (e.g., such as the brain, spinal cord, or aneural ganglion) to a target site. Many microdrive devices have beendeveloped for use in laboratory animals (e.g., FHC microTargetingDrive®, available from FHC, Inc., Bowdoinham Mass.). Radionics(Burlington, Mass.) supplies commercially available microdrives (e.g.,such as the AccuDrive™ drive) suitable for use in human subjects.

Preferably, the microdrive provides easy setting of zero points withreference to a patient's scalp, skull, or dura, for example, andcomprises a carrier unit for receiving the interfacing connector and anadaptor for placing the drive and electrode in a stereotactic frame,which keeps the MC electrode stationary relative to a patient into whichthe electrode is inserted. Preferably, the frame is compatible withperforming analyses by CT, MRI, or a tomographic scanner. In one aspect,the frame also is coupled to a camera apparatus which can obtain opticalinformation from a surgical field and which can correlate theinformation to data relating to the patient's anatomy (e.g., such asobtained by CT and/or MRI), enabling more accurate positioning of the MCelectrode. See, e.g., as described in U.S. Pat. No. 6,275,725.

In another aspect, the drive unit is coupled to a sleeve or telescopingcannula into which the interfacing connector and at least a portion ofthe electrode fits and which can function as a probe housing to protectthe electrode from damage. The drive unit can comprise control elements,for example, advancement knobs, or knobs which control movement of theprobe along an x-, y- or z-axis relative to the stereotactic frame.

However, the drive system also can be coupled to a three-dimensionaldigitizer probe and one or more mechanically articulated arms as inframeless stereotaxy (see, e.g., as described in U.S. Pat. No.6,120,465). For example, a scan of the patient's head may be obtained,and a set of two-dimensional (2-D) scan slices can be collected andinputted into a computer graphic workstation in communication with aprocessor which in turn is in communication with the MC electrode,interfacing connector and drive. The workstation can assemble the 2-Dscan slices and display a three-dimensional representation of thepatient's anatomy (e.g., providing an image of the patient's brain). Thedigitizer probe has an encoding mechanism to provide data relating toits position in space back to the processor, so that when the probe tipis pointed to part of the patient's anatomy, the position of the tiprelative to the three-dimensional representation can be determined. Inthis way mapping between physical and graphic space can be performed andused to guide the movement of the electrode. In one aspect, thedigitizer is a part of a probe housing which contains the MC electrode.

Connections between every channel from the MC electrode connector ontoindividual contact pins on the drive can be accomplished by pointsoldering or silver-plating individual wires from the MC electrodeconnector onto the pins of a drive connector (e.g., the portion of thedrive for receiving the interfacing connector). Preferably, the driveconnector is connected or connectable to a processor which can provideinstructions to the drive unit to control the movement of the MCelectrode in response to signal measurements (e.g., obtained from one ormore recording channel sets or RTQs).

In a chronic treatment regimen, a miniaturized microdrive that canadvance and retract the MC electrode in small amounts is incorporatedinto the interfacing device which is implanted subcutaneously.Preferably, the microdrive also permits rotational movement of the MCelectrode; in this embodiment, the pins of the drive connector alsowould have to be capable of rotational movement. The interfacing devicecan further house recording and stimulating circuitry as describedfurther below.

Amplifiers and Preamplifiers

The MC electrode can be coupled to amplifiers, which are either externalto the interface connector or which are placed within the interfacingconnector housing. Use of an appropriate amplifier may be critical tomaximize signal quality from the small, high impedance sites on the MCelectrode (e.g., such as from recording channel sets or RTQs).Preferably, amplifier gain is 10-100, and more preferably from 10 to1000 times, the signal obtained from the MC electrode. Preferably,amplifiers have built-in common mode rejection. Amplifier circuits alsocan have bandpass filters and even A-D converters microfabricated ontotheir contacts. Preferably, these are all shielded from a patient withinthe interfacing device.

In one aspect, the MC electrode is coupled to a microchip whichcomprises multichannel amplifiers, multiplexing circuitry and,optionally, an RF transmitter (see, e.g., as described in U.S. Pat. No.6,171,239) and which is placed within the interfacing connector housing.Preferably, an amplifier is connected to at least each recording channelset (e.g., such as an RTQ), and more preferably, to each channel of eachrecording channel set. The microchip can be attached to coils permittingpower to be transmitted to the MC electrode via an external power sourceand enabling transmission of multiplexed, multichannel neural signalsout of the MC electrode as a serial data stream. The external power unitfurther can comprise a power coil and a chip for conversion of DCvoltages into the AC voltages. Wireless mechanisms also can be used toestablish a connection to a power source and to relay signals from theMC electrode. For example, radio signals can be used.

Alternatively, or additionally, external amplifiers can be connected toat least each recording channel set of the MC electrode via theinterfacing connector, and more preferably, to each channel of eachrecording channel set. External multichannel amplifier systems are knownin the art and can be connected to the wires of the interfacingconnector (which in turn are connected to central terminals) viacommercially available connector cables or by DIP sockets to which theinterfacing connector is adapted. See, e.g., Bionic Technologies (SaltLake City, Utah) at www.bionictech.com, and Neuralynx (Tuscon, Ariz.) atwww.neuralynx.com. The type of connection will depend on the use of theMC electrode (e.g., whether for an acute or chronic treatment regimen).Preferably, resistors protect the amplifier from damage by staticdischarge and lowers output noise. Still more preferably, amplifiersystems comprise cutoff filters to remove noise from AC signals obtainedfrom the MC electrode which are then converted to DC signals which canbe analyzed by a processor.

In one aspect, both internal amplifiers (i.e., within the interfacingconnector housing) and external amplifiers are provided. Preferably, anexternal amplifier is used to amplify a signal already amplified by theinternal amplifier or “preamplifier”. In one aspect, the preamplifieramplifies a signal 10-50 times (preferably 25 times-50), while theexternal amplifier amplifies the amplified signal another 50-100,000times, preferably, at least 1,000 times.

Typically, recorded neural signals include action potentials or “spikes”(brief, voltage transients) which signal the discharge of small groupsof cells located near the MC electrode recording channel sets. Becausethese cells are of different sizes and distances from the channels,their action potentials will vary in shape and amplitude, and may beseparated electronically or with computer software (e.g., part of thedata acquisition system described further below) on the basis of thesedifferences. Processed signal can be displayed on the display of acomputer workstation in communication with the interfacing connection.

Implantable Stimulator/Recording Device

In one aspect, the MC electrode is used in a chronic treatment regimenand is in communication with an implantable, electrically operatedsource device or stimulator/recording device. Implantable, electricallyoperated neural stimulator/recording systems are known in the art, andhave been used for the control of neural responses to treat intractablepain, epileptic seizures and tremors (e.g., as a result of Parkinsondisease). Signals may be transmitted to the implantable devices fromexternal sources such as RF transmitters. RF-coupled neuromodulationsystems are easily configured to multiple channels where each channelmust be programmed to a different amplitude and which require electricalisolation between the different channels. Further, independent frequencyand pulse width can be achieved easily using an RF-coupled stimulator bysimply alternatively modulating a carrier wave at two (or more)different frequencies, each frequency value designating a pulse widthand rate for a particular channel.

In a preferred aspect, the stimulator/recording device comprises aself-contained power source. For example, one or more batteries can beused. A rechargeable power source with a charging circuit used toconvert RF power received by an inductor into a DC voltage or a pure RFpowered system can be used (such as the MNT/MNR-916CC systemmanufactured by Advanced Neuromodulation Systems, Inc. of Allen, Tex.).Where a battery is used, preferably, the stimulator recording devicealso comprises a micro-controller which monitors battery voltage.

However, more preferably, the system comprises a master controllermodule having a one or more of: a microcontroller, a telemetry circuit,a power module, a memory (preferably, a remotely programmable memory), areal-time clock, a bus (preferably a bi-directional bus), a plurality ofsignal modules which are connected to the bus, and circuitry forconnecting to the individual channels of MC electrode (e.g., via theinterfacing connector).

The signal modules are for inputting signal to the bus and receivingsignal from the bus, and can in turn selectively deliver signal to aplurality of leads which are connected to each channel of MC electrodeand selectively receive signal from each channel. The signal modules arecontrolled by instructions from the microcontroller (received via thebus) which in turn can respond to information from the telemetry circuitand the memory. The real-time clock can be used to control at what pointsignals are delivered from the signal modules to the lead while thetelemetry circuit can respond to outside signals from an instrumentand/or user monitoring the patient into whom the device is implanted.

In one aspect, signal modules are used to deliver stimuli simultaneouslyor sequentially (e.g., according to instructions from the processor) toone or more stimulating/lesioning channel sets or STQs of the MCelectrode. Different stimulus channel sets can be programmed to deliverelectrical pulses having different amplitudes, pulse widths and rates orthe same amplitude, pulse widths, and rates as desired by the user.

In one aspect, signals obtained by one or more signal modules (e.g.,from recording channel sets or RTQs) are stored in a memory containedwithin the device (e.g., a non-volatile memory such as a low voltage,serial EEPROM, which is connected to the micro-controller via the bus)and can, in response to comparison of signals to pre-recorded signals,determine whether to start and/or continue and/or to stop deliveringstimuli to the one or more stimulating/lesioning channel sets. In oneaspect, a user can write into the non-volatile memory when adjustmentsare made to the stimulation parameters. In a preferred aspect, theimpedance of a target site (e.g., neural tissue) is monitored over aperiod of chronic stimulation (see, e.g., as described in U.S. Pat. No.5,941,906) to adjust for changes in impedance which occur as a result ofchronic stimulation.

The MC electrode and implantable stimulator/recording device also can beused in conjunction to determine and control the appropriate amount of adrug or agent to be delivered to a target site. In one aspect, the MCelectrode is used to monitor the electrophysiological responses of oneor more cells to a drug delivered at a target site and in conjunctionwith the master controller, drug/agent delivery is stopped or adjustedin response to this monitoring. For example, when an action potentialfalls below a predetermined value (indicating decreased cellularactivity or death), the telemetry circuit can be used to transmit acommand to an implantable fluid delivery pump (described further below)connected to the MC electrode to deliver a volume of drug to the patientas appropriate or to stop or decrease an amount of drug/agent deliveryif the drug/agent itself is causing deleterious effects. Similarly, whena cell is hyperactivated (e.g., as a result of seizure activity, forexample), the telemetry circuit can be used to transmit a command to thepump to adjust the amount of drug delivered from the MC electrode asappropriate. In one aspect, drug/agent delivery is complemented byelectrical stimulation by stimulating channel sets in proximity to theone or more cells. Predetermined values of neural activity can bedetermined from monitoring the patient during a period when cells havenormal activity or can be determined from the activity of cells in apopulation of normal patients.

Other sensors can be placed in proximity to the MC electrode to enablethe MC electrode to monitor physiological activities that do notnecessarily relate to the electrical activity of cells at a target site.For example, in one aspect, a glucose sensor is provided in proximity tothe MC electrode (e.g., within the lumen of the electrode where thebackbone is hollow or on a probe housing placed over the electrode).Preferably, the output signal of the sensor which corresponds to theglucose level is measured by an AC/DC converter (e.g., in communicationwith the interfacing connector or part of the stimulating system. Whenthe measured glucose level falls below a predetermined value, the mastercontroller telemeters transmit a command to an implantable infusion pumpconnected to the MC electrode to deliver a volume of insulin to thepatient based on the measured level of glucose.

The flow chart shown in FIG. 12 shows a method by which an MC electrodeis implanted at a target site for chronic stimulation of one or moretarget cells. As shown in the Figure, a reading is obtained initially toappropriately localize a target. The electrode is optimally positioned(e.g., by using the drive system described above). The MC electrode andpreferably, the interfacing connector as well, are implantedsubcutaneously at the target site and interfaced with the stimulatordescribed above. Drugs can be delivered to the target site via thehollow portion of the MC electrode.

Although the stimulator device has been described as implantable,external devices are known in the art and can be used. For example, inone aspect, the stimulator device is a device which can be carried in abelt as described in U.S. Pat. No. 6,205,359.

Fluid Delivery Pump

As discussed above, a fluid delivery pump can be coupled to an MCelectrode which comprises a hollow backbone defining a lumen. In oneaspect, the pump is coupled to central opening of the interfacingconnector which receives the MC electrode. Preferably, the pump is partof a pump device which comprises one or more controllers and a memory(e.g., such as an EEPROM memory), a container for containing a fluid,and a drive mechanism for forcing fluid from the container into thelumen of the MC electrode. Preferably, the memory is remotelyprogrammable.

In a preferred aspect, the pump is used to deliver an agent such as adrug, and programmed into the memory provided as part of the pump deviceare delivery parameters related to agent concentration, delivery rate,dose, and bolus size, if appropriate. In one aspect, the container has alabel and the device also comprises a label reader for identifying anagent in the fluid which is being delivered and for triggering thecontroller to run the drive mechanism according to parameters specificfor the delivery of that agent.

Fluid delivery pumps, such as used for drug delivery, and theirassociated control elements, are known in the art, and are described inWO 88/10383; U.S. Pat. Nos. 4,741,732; 6,269,340; and 6,139,539, forexample.

Light Sources and Detector Systems

In a particularly preferred aspect, the backbone of the MC electrodeprovides a light path through which light can be transmitted to a targetsite and received from a target site to image one or more cells at thetarget site. In one aspect, the light path can be provided in the formof a light guide or optical fiber. In another aspect, a plurality ofoptical fibers can be provided (e.g., as bundle within the lumen of ahollow backbone which forms the MC electrode). Bundles of fibers may beused when it is desirable to keep the light transmitting path separatefrom the light receiving path.

Preferably, the light path is coupled to a light source (e.g., anelectromagnetic radiation source (emr), such as a tungsten-halogen lamp,laser, light-emitting diode, and the like). Optical information obtainedfrom the target site can be used to more accurately localize cells inneed of stimulation and/or lesioning. In one aspect, the light path isoperably connected to a detector, (e.g., such as a photodiode) whichdetects one or more optical properties of the illuminated target (e.g.,neural tissue). Optical properties detectable in the useful range of emr(450-2500 nm), include, but are not limited to, scattering (Rayleighscattering, reflection/refraction, diffraction, absorption andextinction), birefringence, refractive index, Kerr effect and the like.

Optical properties can be analyzed by the processor which is incommunication with the interfacing connector and the MC electrode andother external devices in the system and which is described furtherbelow.

Various types of optical detectors may be used, depending on the opticalproperty being detected, the format of data being collected, propertiesof the area of interest, and the type of application, e.g., surgery,diagnosis, monitoring, and the like. Preferably, the optical detectorincludes photon sensitive elements and optical elements that enhance orprocess detected optical signals. Suitable optical detectors include anytype of photon detector, such as photodiodes, photomultiplier tubes,cameras, video cameras, charge coupled devices (CCD), and the like. Onepreferred optical detector for acquiring data in the format of an analogvideo signal is a CCD video camera which produces an output video signalat 30 Hz having, for example, 512 horizontal lines per frame, e.g., suchas a CCD-72 Solid State Camera (Dage-MTI Inc., Michigan City, Ind.) or aCOHU 6510 CCD Monochrome Camera with a COHU 6500 electronic control box(COHU Electronics, San Diego, Calif.). The CCD may be cooled, ifnecessary, to reduce thermal noise.

During optical imaging, a light gathering optical element, such as acamera lens, optical fiber(s), light guide, and the like, can be placedto receive light from a target area and to transmit the light to asuitable detector as described above. Cutoff filters to selectively passall wavelengths above or below a selected wavelength can be employed.The emr source can be directed to a target site by the light path usinga beam splitter controlled by a D.C. regulated power supply (e.g., suchas is available from Lambda, Inc.).

Light may be transmitted continuously to a target site or in pulses. Forexample, non-continuous illumination, such as short pulse (time domain),pulsed time, and amplitude modulated (frequency domain) can be used.Frequency domain illumination sources typically comprise an array oflight source elements, such as laser diodes, with each element modulatedat 180° out of phase with respect to adjacent elements (see, Chance etal., 1993, Proc. Natl. Acad. Sci. USA, 90: 3423-3427). Two-dimensionalarrays of light sources comprising four or more elements in twoorthogonal planes can be employed to obtain two-dimensional localizationinformation (see, e.g., as described in U.S. Pat. Nos. 4,972,331 and5,187,672). A scanning laser beam also may be used in conjunction with asuitable detector, such as a photomultiplier tube, to obtainhigh-resolution images of a target site.

Signals representative of optical properties are produced by thedetector upon receiving light from the light path. These are processedby a processor in communication with the detector and preferably, alsoin communication with the MC electrode and the other external devices ofthe system. Communication with the processor can be centralized throughthe interfacing connector described above. Data representing opticalproperties are displayed on the display of the user device incommunication with the processor. In a preferred aspect, signals fromthe detector are digitized at video speed (30 Hz) and the target isviewed as a digitized image. Analog video signals can be continuouslyprocessed using an image analyzer (e.g., such as a Series 151 ImageProcessor, available from Imaging Technologies, Inc., Woburn, Mass.).

Preferably, consecutive images of target are aligned so that datacorresponding to the same spatial location is compared. Small tissuemovements can be compensated for by either mechanical and/orcomputational means as is known in the art. Larger movements can becompensated for by rigidly securing the detector to a stereotactic framewhere such a device is used. The detector and light source arepreferably provided as an integral unit to reduce their motion relativeto each other. Programs implemented by the processor also can be used toalign corresponding data. Such programs are known in the art and aredescribed in Goshtasby, 1986, In Pattern Recognition 19: 459-66;Wolberg, 1990, “Digital Image Warping” IEEE Computer Society Press, LosAlimitos, Calif., for example.

The optical detector preferably provides images having a high degree ofspatial resolution at a magnification sufficient to detect singleneuronal cells or nerve fiber bundles. Several images can be acquiredover a predetermined time period and combined, such as by averaging, toprovide images which can be displayed on the display of a user device(e.g., a computer workstation) in communication with the processor. In apreferred embodiment, this image is displayed along side, orsuperimposed over, a representation of data obtained by recording theelectrical activity of one or more cells at the target site.

In addition to obtaining optical information to obtain an image of atarget site, optical information can be used to obtain information aboutthe activity of one or more cells at the target site. For example,normally, areas of increased neuronal activity exhibit an increase ofthe emr absorption capacity of neuronal tissue (i.e., the tissue getsdarker if visible light is used for emr illumination, or an intrinsicsignal increases in a positive direction). Similarly, a decrease inneuronal activity is indicated by a decrease of emr absorption capacityof the tissue (i.e., the tissue appears brighter, or intrinsic signalsbecome negative). Both negative and positive intrinsic signals from atarget site which comprises neural tissue can be monitored using thedetector system described above to obtain information relating toneuronal activity. In one aspect, optical information is used to monitorseizure activity at a target site. See, e.g., as described in U.S. Pat.No. 6,233,480.

In a further embodiment, optical imaging is used in conjunction with“electrical imaging” to guide a treatment procedure such as radiationtreatment. For example, in order for radiation treatment to succeed indestroying abnormally proliferating cells such as tumors withoutsignificant harm to a patient, the location of the target of thetreatment must be known precisely, and the radiation source must beaimed precisely at the target. However, it is equally important to knowthe location and function of non-target cells in the vicinity so as toavoid damage to these. Therefore, in one aspect, the one or morerecording channel sets of the MC electrode are used to identify speech,auditory, or visual centers of the brain, to identify cells whichgenerally should not be targeted for treatment. Additionally, oralternatively, the optical imaging system can be used to identify aregion of abnormally proliferating cells which should be targeted fortreatment. For example, tumor cells often produce unique spectralsignals (see, e.g., as described in U.S. Pat. No. 6,104,945) which canbe detected using the optical system.

Processors and Data Acquisition Systems For Signal Analysis

In one aspect, the invention provides a multi-channel data acquisitionsystem and method for the real-time spatial, temporal monitoring andclassification of high frequency bandwidth neuronal activity. Surgicaltargets for the treatment of neurological disorders such as Parkinson's,for example, contain many neurons that have specific neurophysiologicalelectrical properties. Accurate surgical target localization thereforerequires the recording of the electrical “signatures” of as many ofthese neurons as is possible and correlating the electrical signatureswith a patient's symptoms and signs before a lesion is made. The use ofmulti-channel recording electrodes has been shown to increasedramatically the yield of recordable neurons in animals. The task ofaccurately recording the electrical signatures of the neurons that arepicked up by the recording electrodes however, requires a sophisticated,high bandwidth data acquisition system in order to capture the completewaveform of the firing neurons. Although data acquisition systems exist,prior art data acquisition systems have proven to be unsuitable in thisenvironment for large-scale electrophysiological data acquisition.

The present invention provides advantages in that neuronal activity andbehavioral events such as associated motor activity of a subject can berecorded. The sorted and classified neuronal and motor activity data canbe directly inputted to analysis software that performs on-line powerspectral analysis, statistical quantification, and spatial mapping infour-dimensional space (e.g., such as a system similar to the CheetahSoftware by Neurallynx, at www.neurallynx.com). The spatio-temporal andneurophysiological characteristics of the recorded neurons can then beused to provide anatomical information about the structures from whichthe neuronal signals originate thereby allowing the surgical target tobe determined directly. Further detailed analysis of the acquired datacan also be performed off-line. As a result, the data acquisition systemenhances the ability of caregivers and researchers to pinpoint thefunctional relationships of tasks performed by subjects to therespective regions of brain activity.

In one aspect, as shown in FIG. 13, a data acquisition and processingsystem 10 is in communication with an interfacing connector 12, signalprocessing circuitry 14 coupled to the interfacing connector 12, and abehavioral processor 18 communicating with the data acquisition andprocessing system 10. Preferably, the interfacing connector 12 iscoupled to MC electrode 20 which can be acutely or chronically implantedin a subject's brain to pick up neuronal signals of interest (e.g., suchas analog signals). The MC electrode 20 comprises at least one recordingchannel set which can capture a neuronal electrical event simultaneouslyon each of the electrode channels provided within the at least onerecording channel set. Where four channels are provided, a fourdimensional view of a neuronal electrical event may be obtained.

In one aspect, the MC electrode 20 is in communication with aninterfacing connector 12 which includes a preamplifier 24 to amplify aneuronal signal output from the MC electrode 20 (i.e., from one or morerecording channel sets on the MC electrode). Signal can be furtheramplified by one or more amplifiers which are external to theinterfacing connector and which can be received by signal detectors.Signal detectors can include a Schmitt trigger and flip-flop which canprovide a high or low output indicative of whether a signal level hasgone over a predetermined threshold during a selected time period (e.g.,such as a millisecond interval). Signal detector outputs then can bemultiplexed and stored as data in a processor which can convert thesignal into a graphic output and perform one or more statisticaloperations on the signal (e.g., such as histogram analysis). With acompilation of voltage outputs, histograms of electrical activity atmany recording sites may be correlated with stimuli. As a result, theresponse of groups of neurons to stimuli can be studied.

In a preferred aspect, a programmable multiplexer 26 is provided tomultiplex amplified multichannel neuronal signal output of the MCelectrode 20 onto a twisted shielded cable (not shown) to inhibit noisecontamination. Preferably, an isolation element 30 also is providedwhich acts between a power supply 32 and recording channel set(s) of theMC electrode 20 and includes unidirectional buffer circuits that inhibitbackward current leakage from downstream hardware into a subject. Thisdevice 30 can be part of the interfacing connector 12. Thus, theisolation element inhibits ohmic contact between the MC electrode 20 anda target site (e.g., such as a subject's brain) and electricallyseparates the STQ and RTQ. Additionally small optical isolators (notshown) can be provided. These can be incorporated into the interfacingconnector 12 or can be provided as a unit external to the interfacingconnector 12, e.g., where an acute treatment regimen is contemplated.When the system is used in a chronic treatment regimen, it is preferredthat the isolators be provided as part of a subcutaneous unit implantedin a patient.

In one aspect, the preamplifier 24, multiplexer 26, and patientisolation interface device 30, are integrated to form a streamlinedarrangement that facilitates interfacing with a subject. This permitsneuronal activity to be measured in many environments such as theoperating room or chronically. This streamlined arrangement also allowsfor short wire lengths between the preamplifier 24 and the multiplexer26, thereby reducing signal loss and noise contamination. In thisembodiment, multiple “external” devices are made part of a single unitwhich includes the interfacing connector 12, e.g., the devices areexternal to the MC electrode, but are internal within the housing whichcomprises the interfacing connector 12. For example, the interfacingconnector 12 can comprise one or more of a preamplifier 24, A-Dconverter, multiplexer 26, stimulating and recording circuitry,microprocessors, and the like. This type of arrangement is preferredwhen the MC electrode 20 is used in a chronic treatment regimen as itfacilitates the subcutaneous implantation of the interfacing connectorand multiple devices external to the MC electrode.

In one aspect, the interfacing connector 12 is reversibly coupled to aninterfacing cable as described above which can be used to connect theinterfacing connector 12 to devices external to the interfacingconnector 12, e.g., external multichannel amplifiers or stimulatordevices as might be used for an acute treatment regimen, or can beburied at least partially subcutaneously as part of an implanted deviceused for a chronic treatment regimen.

In a further aspect, the signal processing circuitry 14 also includes ademultiplexer 40 that is synchronized with the multiplexer 26. Thedemultiplexer 40 demultiplexes the neuronal signals carried on theshielded cable and outputs the neuronal signals onto output channelscorresponding in number to the input channels of the multiplexer 26. Thesignal processing circuitry 14 also can include an RSI amplifier array42 including high-gain, high bandwidth, programmable differentialinstrumentation amplifiers and software programmable precision bandpassfilters. Filter chips are available from Burr Brown, Texas Instruments,and National Instruments, for example, though they can also becustom-made using methods routine in the art. The amplifiers of the RSIamplifier array 42 amplify the neuronal signals to signal level valuesthat are recognizable by the data acquisition and processing device 10.The bandpass filters of the RSI amplifier array 42 filter the neuronalsignals to selectively eliminate parts of the neuronal signals in orderto highlight measured signal characteristic features. In one aspect, thefilter removes artifacts such as motion artifacts, ground noise, 60 HZsignal noise, and the like.

In one aspect, the RSI amplifier array 42 is highly modularized andincludes multiple amplification cards placed on a common back plane. Abuilt-in regulated power supply (not shown) can be used to providenecessary power to the amplification cards. In one aspect, the backplane can hold up to 12 amplification cards. Preferably, eachamplification card has the capacity to amplify the neuronal signals fromone recording channel set (e.g., such as an RTQ). By addingamplification cards to the back plane, the channel capability of the RSIamplifier array 42 can be increased, making the RSI amplifier arrayscalable.

In another aspect, each amplification card includes two cascadedamplifying stages per channel to preserve the high bandwidth of theneuronal signals. The gain of each amplifying stage can be programmedthrough the data acquisition and processing system 16 and can be set toa gain equal to 1, 10, 100, 1,000 or more. Since each amplification cardprovides two amplifying stages per channel, the amplification factor ofeach amplification card can be set to a gain equal to 1,100, 10,000 or1,000,000, or more. Although currently amplification cards have thecapability of amplifying a signal up to 1,000,000 times, in one aspect,this final amplification value is deliberately inhibited by the dataacquisition and processing device 10, for example, so as not to saturatethe system buffers.

The data acquisition system 10 can be coupled to an IBM compatiblepersonal computer running Windows NT. In one aspect, two high-end dataacquisition cards, such as those manufactured by Innovative Integrationunder number ADC64, are installed in the personal computer. The dataacquisition cards have high-end digital signal processors (DSPs, notshown) as well as eight 16-bit analog to digital converters (ADCs) thatconvert signals from the analog domain to the digital domain.

In one aspect, the personal computer executes data acquisition software.In one aspect, the code of the data acquisition software is split intoat least two components, namely host code and target code. The host codedeals with personal computer functionality while the target code dealswith data acquisition card functionality. The host code runs on thepersonal computer under NT and provides the “front end” or userinterface. The target code runs on the data acquisition cards andperforms “back end” tasks.

In one aspect, the target code is written in TI C32 DSP Assembly and C.The portion of the target code written in C handles low speed systemsetting issues and initialization. The portion of the target codewritten in Assembly runs in a tight loop and forms the basis for a dataacquisition algorithm. The data acquisition algorithm is responsible forthe task of sampling and multiplexing neuronal signals output by the RSIamplifier array 42 into the ADCs. The Assembly target code also performs“thresholding”. Thresholding ensures that the data acquisition cardsgrab data from the ADCs only if the amplitudes of the neuronal signalsreceived from the RSI amplifier array 42 swing above or below auser-defined threshold. User-defined thresholds will depend on thetissue being recorded from, e.g., the type of neuron being evaluated,its firing properties, etc., as well as on whether the tissue isphysiologically normal or involved in a disease process.

In addition, the target code accesses pre-established neuronal signalpatterns stored in memory. The target code can be conditioned to comparesampled neuronal signals with the pre-established neuronal signalpatterns and generate scores reflecting the degree of similarity betweensampled neuronal signals and the pre-established neuronal signalpatterns.

In one aspect, the host code is written in Visual C++ and provides auser with control options via a graphical user interface. The host codecan grab data sent to it by the target code, analyze and plot the dataand save the data to hard disk on cue from a user command. The plotsgenerated by the host code show neuronal signal waveforms and the powerspectrum of the neuronal signal waveforms. Additionally, the host codeallows the user to set the gains on the data acquisition cards, thegains for the amplifiers of the RSI amplifier array 42, the bandpassfilter cut-off frequencies for the RSI amplifier array 42 and the activeinput channels of the multiplexer 26. In this embodiment, the upper andlower cut-off frequencies of the bandpass filters can be programmed inthe range from about 9 kHz to 100 Hz. The host code also allows the userto set the target code threshold.

In one aspect, a behavioral processor 18 is provided which communicateswith a plurality of sensors 66 which monitor a subject under observationas the subject performs physical tasks, and records one more physicalconditions of the subject during task performance. In this particularembodiment, the sensors 66 include a video recorder, an audio recorderand accelerometers to measure limb movement. Those of skill in the artwill, however, appreciate that other types of sensors can be used tomonitor the subject. The behavioral processor 18 triggers the dataacquisition and processing device 10 so that neuronal activity dataacquisition is synchronized with the behavioral events of the subjectthat are recorded by the behavioral processor 18.

During initialization, the host code of the data acquisition system 10checks for the presence of the data acquisition cards in the personalcomputer. When the data acquisition cards are present, the host codedownloads the target code onto the data acquisition cards and sets up a“handshaking” mechanism between the host code and the target code toenable data and command transfer between the host code and the dataacquisition cards.

During operation, an MC electrode 20 is implanted at a target site, suchas in the subject's brain. In a preferred aspect, the MC electrodecomprises at least one recording channel set comprising four electrodesor an RTQ which can acquire neuronal activity at target site in fourdimensions. Sensors 66 are also initialized to monitor behavioral eventsof the subject under observation. The subject is then requested toperform tasks. During task performance, the behavioral processor 18records the output of the sensors 66. The behavioral processor 18 alsosends “acquire” and “stop-acquire signals to the data acquisition deviceand processing device 10 at selected times during task performance sothat neuronal activity, corresponding to selected instances of subjectmotor activity, is acquired over the desired durations. These durationsmay be from several seconds to several minutes in duration.

During task performance, the neuronal signal output of the MC electrode20 is conveyed to the preamplifier 24. The preamplifier 24 in turnamplifies the neuronal signals to signal levels in the range of fromabout 0 to ±10 V to reduce signal loss either by decreasing the outputimpedance to increase current or by providing gain to increase voltageand current. The amplified neuronal signals output by the preamplifier24 are applied to the input channels of the multiplexer 26. The neuronalsignals received on the active input channels of the multiplexer 26 aremultiplexed onto the shielded twisted cable before being conveyed to thepatient isolation interface device 30. As mentioned previously, thepatient isolation interface device 30 inhibits ohmic contact between theMC electrode 20 and the subject's brain.

The neurons signal output of the patent isolation interface device 30 isconveyed to the demultiplexer 40 via the cable and demultiplexed ontoits output channels. The RSI amplifier array 42 in turn boosts thesignals appearing on the output channels of the demultiplexer 40 byproviding EMI and RF noise regeneration in the neuronal signals inaccordance with the values assigned to the programmable gains of theamplifiers by the data acquisition and processing device 10. The RSIamplifier array 42 also removes selected pans of the neuronal signalsvia the bandpass filters as programmed by the data acquisition andprocessing device 10. The amplified and filtered neuronal signals outputby the RSI amplifier array 42 are then conveyed to the data acquisitionand processing device 10.

When the data acquisition and processing device 10 are triggered by anacquire signal from the behavioral processor 18, the target code isexecuted. When the target code is executed, the data acquisition cardsstep through the data acquisition algorithm. During this algorithm, theneuronal signal output of the RSI amplifier array 42 is sampled at arate equal to about 30 kHz (resultant) and the neuronal signals aremultiplexed into the ADCs. The neuronal signals are in turn digitized bythe ADCs. During execution of the target code, thresholding is alsoperformed by comparing the digital values output by the ADCs with theuser set threshold.

If the digital values on one or more of the RSI amplifier array outputchannels swing above or below the threshold signifying potentiallyrelevant neuronal signals, the data acquisition cards capture thedigital values for a predetermined period of time, in this example 1-2msecs. Specifically, the data acquisition cards store the previous eightsampled values in addition to the next twenty-four (24) sampled values.This is achieved by using circular buffers to store the sampled datawhile it is being acquired. For the acquisition of data to take place at30 kHz, the Assembly target code performs an acquisition once every 90KHz. If the target code is conditioned to compare incoming neuronalsignals with the pre-established neuronal signal patterns stored inmemory, the target code compares the digital values with each of thestored patterns and generates scores. The sampled digital values, thethreshold information signifying the transducer that generated theneuronal signal which caused the digital value to be sampled, and thescores, if calculated, form a data packet.

In one aspect, once seven data packets are grabbed by the dataacquisition cards, the data packets are transferred in bursts or streamsto the host code via a PCI bus within the personal computer and storedin permanent memory. A burst is sent per PCI bus mastering operation fora total data throughput of 20 Mbs, a rate well under the permissible PCIbus transfer limit of 68 Mbs.

The host code in turn processes the data on-line by performing powerspectral analysis, statistical quantification and spatial mapping infour dimensions. Thus, real time feedback can be provided to improvesurgical targets and to modify the active channels of the multiplexer26. The data stored in memory can also be downloaded to an off-lineneural data analysis system for further processing.

When the duration of the relevant behavioral event has expired, thebehavioral processor 18 sends a “stop-acquire” signal to the dataacquisition and processing device 10 causing it to stop the dataacquisition. At this point the neuronal signals output by the MCelectrode 20 is no longer recorded.

The above-described form of data gathering accomplishes two goals.First, the temporal sequence of neuron firing is clearly establishedrelative to the stages of the behavioral event of interest. Secondly,the spatial location of each of these neurons firing in sequence isclearly established by the bundled electrodes of the recording probes.The collected data is readily available for processing by data analysistechniques to yield insight into the nature of the neural activity inrelationship to behavioral patterns. This immediate data analysis can beused to determine the properties of recorded neuronal activity andtherefore, increase the accuracy of surgical targets, which aids inpatient treatment.

Methods of Using MC Electrodes

The quality of data about neuronal group interactions obtained frommultichannel electrodes is directly related to the number ofsimultaneous recordings made. It is desirable, for example, to sense theelectrical activity of neurons at twenty or more sites through thecortex, the outer layer of the brain. The simultaneous response ofneighboring neurons to stimuli provides a greater insight into the groupinteraction of neurons and a more detailed characterization of a targetsite for stimulation and/or lesioning or drug delivery.

The MC electrode according to the invention is particularly suitable forsensing electrical activity of brain tissue at a plurality of sitesbecause its volume is small enough to minimize damage to the tissue. Theincreased number of sites which can be tested without trauma to thebrain increases the efficiency of neurosurgical procedures since targetscan be localized more effectively and safely.

The recording and stimulation function of the MC electrode alsofacilitates automatic feedback control by a processor in communicationwith the MC electrode. This technique, which is well known to thosespecialized in the treatment of epileptic seizures, involves monitoringbrain activity signals and accurately identifying aberrant electricactivity. After analysis, electrical current is administered back to thebrain in opposition to the original aberrant level so that the netresultant voltage, current and/or electrical field in localized areas onthe brain is maintained at no level greater than that experiencednormally. Because the MC electrode can be implanted (vs. used at thesurface of the brain), electrical signals from target cell(s) can berecorded by the recording channel set(s) of the electrode without anydeterioration of signal (e.g., such as due to the impedance of thefluids, tissue, skull bone and other media between the target site andelectrode as would occur when using a surface electrode). Similarly, acontrol signal for feedback data, if applied externally, would require alarger electrical signal to produce a comparable control.

Typical electrical voltages represented in medical research studiesreveal that, when monitored internally, a normal brain pattern signalcan reach 10 millivolts while the same signal monitored outside theskull produces a level of approximately 10 microvolts. For example, theaura condition of an epileptic seizure can in fact increase theelectrical activity a factor of 10 times to a level 100 millivolts (whenmonitored internally). Hence, for a corrective signal to be applied inopposition to such an aberrant level, a minus 90 millivolts level wouldbe internally applied whereas approximately minus 90 volts would beexternally applied; a quantity which could be dangerous. Therefore, MCelectrodes provide optimal voltage control at low levels that are safe.

The type of stimulation delivered by the MC electrode depends on thespecific location at which the electrode is surgically implanted and thedesired action on cells at that location. Preferably, the MC electrodedelivers stimuli having amplitudes of 0.1 to 20 volts, pulse widthsvarying from 0.02 to 1.5 milliseconds, and repetition rates varying from2 to 2500 Hz. If the cell is a neuron and activity is to be blocked,preferably, the frequency of the stimulus is in the range 50 to 2500 HZ.If the neuronal activity is to be increased, the frequency ispreferably, in the range of 2 to 100 Hz. The invention thereforeprovides a method of monitoring the activity of one or more cells at atarget site by recording electrical potentials of the one or more cellsand/or modulating the activity of one or more cells. In one aspect, themethod comprises bringing an MC electrode, as described above, inelectrical proximity to the one or more cells and recording the activityof the one or more cells using at least one recording channel set (e.g.,such as an RTQ) of the MC. Preferably, this recorded activity iscompared to the activity of a cell with one or more known physiologicalproperties (e.g., a non-diseased neural cell). In one aspect, therecorded activity is used to determine the anatomical location of one ormore malfunctioning cells. In a preferred aspect, after determining theanatomical location of the one or more malfunctioning cell, at least oneother set of channels (e.g., a stimulating/lesioning channel set, suchas an STQ) is activated to deliver an electrical stimulus to the one ormore cells. This may require repositioning the MC electrode prior tostimulation and recording at a new position to validate that a targetcell(s) is in suitable electrical proximity to a stimulating/lesioningchannel set or STQ. In one aspect, the stimulus is used to activate theone or more cells. In another aspect, the stimulus is used to inhibitthe one or more cells. In a further aspect, the stimulus is used todisable or lesion the one or more cells.

Preferably, a processor in communication with the MC electrode is usedto control the movement and activity of the electrode. In a particularlypreferred aspect, the MC electrode is used to image a target site andthe processor moves and/or alters the activity of the electrode inresponse to an image obtained (i.e., automatically and/or or in responseto instructions from a user).

For example, in one aspect, the MC electrode is used in an acutetreatment by bringing the MC in proximity to one or more cells,localizing target cells in need of such treatment (e.g., using at leastone RTQ), bringing the MC in closer proximity to the cells if necessary,activating or inhibiting the activity of the target cells or disablingthe target cells (e.g., using at least one STQ) and removing the MCelectrode from the proximity of the target cells.

In another aspect, the MC electrode is used in a chronic treatment bybringing the MC in proximity to one or more cells, localizing targetcells in need of such treatment (e.g., using at least one RTQ), bringingthe MC electrode in closer proximity to the cells if necessary, andactivating or inhibiting the activity of the target cells (e.g., usingat least one STQ). Preferably, the MC electrode remains in proximity tothe target cells to monitor the activity of the target cells andstimulating the cells as necessary to maintain a desired state of thecells.

In a particularly preferred aspect of the invention, the MC electrode isused to treat Parkinson's disease. Parkinson's disease is aneuropathological condition of unknown etiology which afflictsapproximately 1 million individuals in the U.S. alone. Symptoms includea decreased spontaneous movement (bradykinesia), rigidity, and tremor,which in many cases can be very disabling.

In one aspect, therefore, the method comprises inserting an introducertube (e.g., contained within a stereotactic frame) into the brain of apatient having Parkinson's disease such that the distal end of the tubeis positioned close to the target tissue (e.g., as determined by CT, MRor a tomographic scanning method). An MC electrode according to theinvention is next introduced into the introducer tube and is connectedto a drive mechanism as described above via the interfacing connector.The tip of the electrode is advanced and the degree of advancement maybe adjusted in based on information about optical properties of thetarget site obtained from a detector in communication with a light path(e.g., optical fiber) provided either within the MC electrode backboneor as part of the MC electrode backbone. These optical properties arethen converted into an image on the display of a user device incommunication with a processor which in turn is in communication withthe detector, interfacing connector, and drive for controlling themovement of the MC electrode.

Preferably, the MC electrode is driven through a trajectory defined bythe processor within the globus pallidus of the brain based oninstructions from a user upon viewing the image and displays ofelectrical signals obtained from RTQ channels of the MC electrode. TheMC electrode is used to monitor the physiological activity of at leastone neuron within the globus pallidus within the vicinity of the MCelectrode using at least one recording channel set (e.g., RTQ). Inresponse to this monitoring, the processor can then inactivate the atleast one neuron by applying an appropriate degree of stimulation to theat least one neuron (see, e.g., as described in Lehman et al., 2000,Stereotact. Funct. Neurosurg. 75(1): 1-15).

For example, the MC electrode can be used to identify the abnormal cellsin the globus pallidus interna and subthalmic nucleus, and/or in thepedunculopontine nucleus in a patent with Parkinson's disease by theirhigh frequency of firing (e.g., 30-120 Hz) and these cells can beinactivated by applying a electrical discharge from one or morestimulating sets of the MC electrode in a frequency range of from 50-200Hz, with a voltage range of 1-5V, and currents in the 100-500 μAmprange.

In addition to inactivating cells, different levels of stimulation maybe used to prevent or reduce excitatory damage caused by high firingrates. Hence, in addition to helping symptoms directly, stimulation mayalso help slow down the progression of disease. In addition, the abilityto micro-stimulate using recording channel set(s) of the MC electrodecan help identify areas around the electrode that are vulnerable andshould be avoided. Lesioning in several areas that are consistentlyactive also can be performed using the MC electrode. The areas targetedcan be single or multiple.

Administration of growth factors through the hollow portion, along withtissue suspensions may also help treat and reverse the difficulties inParkinson's disease. In this scenario, multiple injections intophysiologically defined areas can be made. If the MC electrode is leftin situ, the injections can be carried out over a period of time insteadof having to re-perform surgery.

In addition to Parkinson's disease, electrode stimulation has been usedto treat a number of different diseases including, but not limited to:motor dysfunction (see, e.g., U.S. Pat. No. 6,175,769); spasticity (see,e.g., Lin, 2000, Neurorehabil. Neural Repair 14(3): 199-205; Davis,2000, Arch. Med. Res. 31(3): 290-9); tremors (Krauss et al., 2001,Neurosurgery. 48(3): 535-41; discussion 541-3); dystonia (see, e.g.,Krack, 2001, Eur. J. Neurol. 8(5): 389-99); mood disorders (see, e.g.,U.S. Pat. Nos. 6,263,237; 6,167,311); hypothalmic obesity (see, e.g.,U.S. Pat. Nos. 5,540,734; 5,443,710; and U.S. Pat. No. 4,646,744);incontinence (see, e.g., U.S. Pat. No. 5,314,465); stroke (see, e.g.,U.S. Pat. No. 6,221,908); epilepsy (see, e.g., U.S. Pat. No. 6,205,359);chronic pain (see, e.g., Van Buyten et al., 2001, Eur. J. Pain 5(3):299-307); spinal cord injuries (Prochazka et al., 2001, J. Physiol.533(Pt 1): 99-109).

The invention contemplates that the MC electrodes according to theinvention can be used in methods of treating these disorders by bringingan MC electrode in proximity to a target site (as identified in any ofthe above references), recording electrical signals of cells at a targetsite to identify cells with abnormal electrical activity (as described,for example, in any of the above references) and delivering anappropriate amount of electrical stimulation to restore the electricalactivity of the target cells to a predetermined normal level (e.g., asdescribed in the references above or as determined by monitoring theactivity of cells during a period of normal physiological activity or bymonitoring cells which neighbor a target site and which display normalphysiological activity).

For example, thalamic stimulation or lesioning by the MC electrode canbe used for modulation of tremor. Tremor cells, identified behaviorallyin the operating room and chronically as having higher frequency offiring and rhythmically related to the tremor, may be recorded using theMC electrode. Once identified, stimulation or lesioning at multiplesites can be performed to reduce the output of these cells, therebyproducing an arrest of tremor.

In another aspect, abnormal firing of cells in the cortex can bedetermined as a means of identifying seizure activity in patients withepilepsy. Micro-stimulation can be performed in the areas to reproducesymptoms, such as epileptic auras. In addition, the border zones ofareas of abnormality can be identified well. This procedure currentlyrequires open craniotomy. In one aspect, multiple small MC electrodesaccording to the invention can be navigated underneath the skull througha small opening. The visualization capability of the MC electrodes(e.g., the presence of one or more light paths, cameras, and or lens,which are part of, or internal to, the backbone) allows preciseplacement of the MC electrodes. Central guide wiring can be placed toallow manipulation of the electrodes. The electrode(s) can then be leftin place if necessary, once region(s) of interest are identified. Thisprocedure may allow the surgeon to preserve brain tissue instead ofhaving to take the epileptogenic areas out.

Additionally, drugs that reduce epileptic potential can be administeredonce physiologically active areas are identified. These areas may notsimply be in the cortex, but also may be in other structures such as thethalamus, hippocampus, other deep brain structures, vagal nerve, and thelike, that provide an origin for the epileptic spikes.

The MC electrode according to the invention also can be used toimplement tumor surgery. For example, abnormal tissue can be identifiedusing the optics of the electrode (e.g., surface and deep tumors,ventricular tumors, and the like). Additionally, or alternatively, thetumor cells may demonstrate particular electrical signatures which canbe identified using recording channel sets of the electrode andcorrelated with the presence of abnormal cell proliferation. In oneaspect, suction is applied through the hollow central core of the MCelectrode and fluid is withdrawn through the core, to provide one ormore samples to test for the presence of tumor markers.

Electrically normal cells also can be identified to mark the borders ofthe tumor through the placement of multiple MC electrodes. This isespecially useful to identify areas adjacent to abnormally proliferatingcells which may have critical functions, e.g., such as the visual orspeech control centers of the brain. Once the tumor is properlyidentified, lesioning or administration of chemotherapy or radiationtherapy is feasible. This is dependent on factors such as the tumor celltype, its location and its chemo and radiosensitivity.

In addition to using the MC electrode in methods of treatment, the MCelectrode can be used to detect the presence of, or monitor theprogression of, abnormal physiological activity in a cell. In oneaspect, the target site is the brain and the MC electrode is used todetect the presence of abnormal activity in target sites such as theLocus Ceruleus; Amygdyla; Nucleus of Thalamus; subthalamus; subthalamicnucleus; pedunculopontine nucleus; Dorsal raphe Nucleus; Septum; Cortex;hippocampus, Anterior Thalamus; Mamillary body, Globus Pallidus, cranialnerve (e.g., the vagus nerve), and the like. In another aspect, thetarget site is the spinal cord. In a further aspect, the MC electrode isused to monitor the electrical activity of cells at a target site inorder to control drug delivery to the target site.

EXAMPLE

The invention will now be further illustrated with reference to thefollowing example. It will be appreciated that what follows is by way ofexample only and that modifications to detail may be made while stillfalling within the scope of the invention.

Example 1 Design and Testing of Four Channel Prototype Electrodes

A gold plated copper-backed flex circuit board was first glued onto agold-coated metal rod backbone. Three of the four channels wereprecisely machined using a depth control machining technique on thecircuit board leaving the underneath plastic insulating material intact.The board was then mounted on to a 0.5 mm diameter gold-coated metal rodbackbone with a fourth channel machined on it. Electrode connector padswere attached to wires for data measurements (see, FIG. 4). The machinedwidth of the individual channels of the electrode was 15±2 μm. Theelectrode was then partially covered with an insulating plastic materialleaving 4±1 μm of the tip uninsulated. The spacing between the fourchannels at the tip was 20±5 μm (see, FIG. 5).

To determine the amount of current deliverable through fine wirecross-sections of varying diameters measurements were initiallyperformed on 25 μm and 37.5 μm diameter copper-gold flex backboneshaving channels whose widths ranged from 12 μm to 65 μm (see, FIG. 6).The maximum possible current was passed through each conductor width foreach type of backbone. Even with a minimal channel width of 12 μm, asingle channel could withstand continuous current levels as high as 250mA and 460 mA for conducting materials thickness of 25 μm and 37.5 μm,respectively. This current quantity is more than sufficient to stimulateor produce lesions.

Voltages versus current characteristics were tested for each independentchannel (see, FIG. 7) and the measured voltage with respect to input wasplotted for each channel. Each individual channel of the electrode wasused as a cathode with a copper cylindrical support as the anode. Thecompleted assembly was inserted into salt solution for data measurements(see insert in FIG. 7). As shown in FIG. 7, there is a linearrelationship between the voltage and current in the channels of the MCelectrode. The measurements also indicate chat it is indeed possible touse current levels beyond 10 mA through each individual channel of theelectrode. Additional measurements were carried out using a platinumelectrode as anode and the measured data showed a linear increase in thecurrent levels >30 mA (data not shown).

The MC electrode was then tested in a rodent to determine its ability torecord in vivo neuronal signals. An anesthetized animal was preparedaccording to procedures well known in the art (see, FIG. 8) and theelectrode was inserted into the brain of the animal (FIG. 9). Theoutputs of the electrode were connected to the data acquisition systemdescribed herein.

A typical neuronal recording is shown in FIG. 10. The Figure shows thatthe four-channel MC electrode is capable of passing significant amountsof current into the brain of an animal for recording neural signalsand/or for stimulating and/or lesioning neural cells at a target site.Multiple four-channel bundles with individual channels for stimulationand recording can be fabricated on an MC electrode.

Variations, modifications, and other implementations of what isdescribed herein will occur to those of ordinary skill in the artwithout departing from the spirit and scope of the invention.

All of the references identified herein, are hereby expresslyincorporated herein by reference.

1. A method of fabricating a multichannel electrode, said methodcomprising the steps of: a) providing a first non-planar backbonecomprising a lumen; b) coating said non-planar backbone with anelectrically conductive material; c) laser micro-machining a pluralityof channels into said electrically conductive material; d) providing asecond non-planar backbone within said lumen of said first non-planarbackbone, said second non-planar backbone coated with an electricallyconductive material and comprising a plurality of electrode channelsmachined thereon; wherein at least one channel of said multichannelelectrode comprises an impedance suitable for recording electricalactivity of a cell, and wherein at least one channel comprises animpedance suitable for stimulating the electrical activity of a cell;and (e) placing said second backbone within said lumen of said firstbackbone.
 2. A method of fabricating a multichannel electrode, saidmethod comprising the steps of: a) providing a first non-planar backbonecomprising a lumen; b) coating said non-planar backbone with anelectrically conductive material; c) laser micro-machining a pluralityof channels into said electrically conductive material; d) providing asecond non-planar backbone comprising a lumen within said lumen of saidfirst non-planar backbone, said second non-planar backbone coated withan electrically conductive material and comprising a plurality ofelectrode channels machined thereon; wherein at least one channel ofsaid multichannel electrode comprises an impedance suitable forrecording electrical activity of a cell, and wherein at least onechannel comprises an impedance suitable for stimulating the electricalactivity of a cell, and/or lesioning a cell; and (e) placing said secondbackbone within said lumen of said first backbone.
 3. The method ofclaim 1 or 2, wherein said impedance suitable for stimulating theelectrical activity of a cell is less than or equal to 200 kilo ohms. 4.The method of claim 1 or 2 wherein said impedance suitable for recordingelectrical activity of a cell is from 200 kilo ohms to one megaohm. 5.The method of claim 1 or 2, wherein said impedance suitable forlesioning that is less than or equal to 200 kilo ohms.